Anti-cancer nuclear hormone receptor-targeting compounds

ABSTRACT

The disclosure relates to anti-cancer compounds derived from nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/935,065, filed Nov. 13, 2019, which is hereby incorporated by reference in its entirety.

BACKGROUND

The disclosure relates to anti-cancer compounds derived from nuclear receptor binders, such as nuclear steroid receptor binders, to products containing the same, as well as to methods of their use and preparation.

PARP inhibitors are pharmacologic agents that prevent DNA repair leading to the death of cells and hence tumor growth inhibition. This mechanism of preventing cell growth leads to significant anti-tumor activity in tumors with BRCA1, BRCA2 and PALB2 mutations, as these proteins are important for the repair of double strand DNA breaks by the homologous recombinant repair (HRR) pathway. Normal cells that are not dividing as fast as tumors and do not carry mutated BRCA1 or BRCA2 still have the HRR pathway intact which allows them to survive in the face of PARP inhibition. In addition to the catalytic inhibition of PARP, researchers at the National Cancer Institute in 2012 discovered an additional mechanism that drives the toxic effect of PARP inhibitors in tumor cells. Their observation that in addition to the blockade of the enzymatic activity of PARP, certain PARP inhibitors have the ability to localize PARP proteins to sites of DNA damage, correlated with the cytotoxicity of these inhibitors. This mode of action, called “PARP trapping” is an additional mechanism by which this class of pharmacologic agents works in the preventing tumor growth and survival (Murai, et al. Cancer Research (2012) 72(21): 5588-99). Inhibitors of PARP enzymes (such as olaparib, rucaparib, niraparib, and talzoparib) have been approved for the treatment of breast cancer in patients with BRCA mutations, and ovarian cancer. There are several others (e.g., velaparib) that are in clinical testing for breast, prostate and ovarian cancers. The use of PARP inhibitors is not without side effects, and one of the major road blocks to the long-term use of PARP inhibitors is the rapid and dose dependent development of neutropenia. This requires dosing holidays and/or dose reductions in clinical practice, which compromise the ability to achieve maximal efficacy.

SUMMARY

Provided herein are compounds comprising a nuclear payload and a nuclear receptor-targeting epitope. Compounds described herein are designed to bind nuclear receptors within the cell and allow the compound, with its nuclear payload, to accumulate in the nucleus. Not wishing to be bound by theory, one potential mode of enhanced utility is that this approach may provide for compounds having cell-type selectivity, not merely improved potency, working toward a higher therapeutic index. However, it may be that the compounds may be active by other modes, such as, but not limited to, passive localization in the nucleus.

Further, the compounds described herein offer targeted delivery of a nuclear payload. The compounds both target and localize within tumor tissue. The transport of the compound, which comprises at least one nuclear receptor-targeting epitope, such as a nuclear steroid receptor-targeting epitope, covalently attached to at least one nuclear payload, to the nucleus allows for accumulation of the nuclear payload in the nucleus, enhancing tumor cell death. By doing so, compounds described in this disclosure may exhibit superior efficacy. In addition, the compounds described in this disclosure will, by accumulating preferentially in the nucleus of nuclear receptor positive cells, such as steroid receptor positive cells, spare cells that do not express the specific nuclear steroid receptor, and therefore reduce side effects.

Provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-(L-B)_(m)  I

A-L-(B)_(m)  II

wherein:

A is a nuclear payload;

m is 1, 2 or 3;

each B is independently a nuclear receptor-targeting epitope; and

each L is independently a covalent bond or a linking moiety; provided that at least one L is selected from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L45, and L46, and/or at least one B is selected from B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, and B19:

and further wherein the “*” in L denotes a covalent bond between A and L, and the wavy line in each L and B denotes a covalent bond therebetween.

In certain embodiments, A is A1, A2, A3, or A4:

wherein the “*” in each A moiety indicates the point of attachment to L.

In certain embodiments, provided is a compound comprising at least one nuclear payload and at least one nuclear receptor-targeting epitope. In certain embodiments, when the compound comprises one nuclear payload and one nuclear receptor-targeting epitope, the nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody. In certain embodiments, when the compound comprises one nuclear payload and one nuclear receptor-targeting epitope, where the nuclear receptor-targeting epitope is an androgen receptor-targeting epitope or an estrogen receptor-targeting epitope, the nuclear payload is not doxorubicin, or an analog thereof. In certain embodiments, when the compound comprises one nuclear payload and one nuclear receptor-targeting epitope, where the nuclear receptor-targeting epitope is an androgen receptor-targeting epitope or an estrogen receptor-targeting epitope, the nuclear payload is not a hydroxamic acid which binds histone deacetylase (HDAC).

In certain embodiments, provided is a compound comprising at least one nuclear payload and at least one nuclear receptor-targeting epitope; provided that when the compound comprises one nuclear payload and one nuclear receptor-targeting epitope:

the nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody; and

when the nuclear receptor-targeting epitope is an androgen receptor-targeting epitope or an estrogen receptor-targeting epitope, the nuclear payload is not doxorubicin, or an analog thereof, and is not a hydroxamic acid which binds histone deacetylase (HDAC).

In certain embodiments, provided is a compound comprising at least one nuclear payload which binds to a catalytic domain of poly(ADP-ribose) polymerase (PARP) and at least one nuclear receptor-targeting epitope. In certain embodiments, the at least one nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope.

In certain embodiments, provided is a compound comprising at least one nuclear payload which binds to a poly(ADP-ribose) polymerase (PARP) (e.g., PARP-1 and/or PARP-2) and at least one nuclear receptor-targeting epitope. In certain embodiments, provided is a compound comprising at least one nuclear payload which binds to a poly(ADP-ribose) polymerase (PARP) (e.g., PARP-1 and/or PARP-2) and at least one estrogen receptor-targeting epitope, glucocorticoid receptor-targeting epitope, progesterone receptor-targeting epitope or androgen receptor-targeting epitope.

In certain embodiments, provided is a compound comprising at least one nuclear payload which binds to poly(ADP-ribose) polymerase (PARP) (e.g., PARP-1 and/or PARP-2) and at least one nuclear receptor-targeting epitope derived from an androgen receptor agonist, an androgen receptor antagonist, a selective androgen-receptor modulator (SARM), an estrogen receptor agonist, an estrogen receptor antagonist, a selective estrogen receptor modulator (SERM), a selective estrogen receptor modulator (SERM), a glucocorticoid receptor agonist, a glucocorticoid receptor antagonist, a selective glucocorticoid receptor modulator (SGRM), a progesterone receptor antagonist, a progesterone receptor agonist, a selective progesterone receptor modulator (SPRM), or a combination thereof.

In certain embodiments, provided is a compound comprising at least one nuclear payload which binds to poly(ADP-ribose) polymerase (PARP) (e.g., PARP-1 and/or PARP-2) and at least one nuclear steroid receptor-targeting epitope derived from an androgen receptor agonist, an androgen receptor antagonist, a selective androgen-receptor modulator (SARM), an estrogen receptor agonist, an estrogen receptor antagonist, a progesterone receptor antagonist, a progesterone receptor agonist, a selective progesterone receptor modulator (SPRM), or a combination thereof.

In certain embodiments, provided is a compound comprising at least one nuclear payload which binds to a poly(ADP-ribose) polymerase (PARP) (e.g., PARP-1 and/or PARP-2) and at least one nuclear receptor-targeting epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof.

In certain embodiments of Formula I or II, when m is 1, the nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody. In certain embodiments of Formula I or II, when m is 1, and B is an androgen receptor-targeting epitope or an estrogen receptor-targeting epitope, then A is not doxorubicin, or an analog thereof. In certain embodiments of Formula I or II, when m is 1, and B is an androgen receptor-targeting epitope or an estrogen receptor-targeting epitope, then A is not a hydroxamic acid which binds histone deacetylase (HDAC).

Also provided is a compound of Table 1, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

Also provided is a composition comprising a compound as described herein or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

Also provided is a method of treating or preventing cancer, comprising administering an effective amount of a compound or composition as described herein to an individual in need thereof. The cancer can be a blood cancer, lung cancer, breast cancer, fallopian tube cancer, brain cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer or skin cancer, such as, but not limited to, liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma.

Also provided is a method of treating or preventing bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer, comprising administering an effective amount of a compound or composition as described herein, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need thereof.

Also provided is a method of treating or preventing cancer a expressing the androgen receptor (also known as an androgen receptor-positive cancer, or AR+ cancer), comprising administering an effective amount of a compound or composition as described herein to an individual in need thereof. In some embodiments, the androgen receptor-positive cancer is an androgen receptor overexpressing cancer, or an androgen receptor overexpressing tumor.

Also provided is a method of treating or preventing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one nuclear receptor-targeting epitope comprising testosterone, a testosterone ester (e.g., testosterone enanthate, propionate, cypionate, etc., or an analog thereof), enobosarm, BMS-564929, PS178990, LGD-4033 (ligandrol), LGD-2941, AC-262,356, JNJ-28330835, JNJ-37654032, JNJ-26146900, LGD-2226, LGD-3303, LGD-121071, LG-120907, S-40503, S-23, RAD-140, acetothiolutamide, andarine (S-4), LG-121071, TFM-4AS-1, YK-11, MK-0773 (PF-05314882), GSK2849466, GSK2881078, GSK8698, GSK4336, ACP-105, TT701, LY2452473, a 1-(2-hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitrile-derivative (J Med Chem. 2014, 57(6), 2462-71), anordrin, bazedoxifene, broparestrol (Acnestrol), clomifene (Clomid), cyclofenil (Sexovid), lasofoxifene (Fablyn), ormeloxifene (Centron, Novex, Novex-DS, Sevista), ospemifene (Osphena, deaminohydroxytoremifene), raloxifene (Evista), tamoxifen (Nolvadex), toremifene (Fareston; 4-chlorotamoxifen), acolbifene, afimoxifene (4-hydroxytamoxifen; metabolite of tamoxifen), elacestrant, enclomifene ((E)-clomifene), endoxifen (4-hydroxy-N-desmethyltamoxifen; metabolite of tamoxifen), zuclomifene ((Z)-clomifene), bazedoifene, arzoxifene, brilanestrant, clomifenoxide (clomiphene N-oxide; metabolite of clomifene), droloxifene (3-hydroxytamoxifen), etacstil, ospemifene, GW-7604 (4-hydroxyetacstil), idoxifene (pyrrolidino-4-iodotamoxifen), levormeloxifene ((L)-ormeloxifene), miproxifene, nafoxidine, nitromifene (CI-628), panomifene, pipendoxifene (ERA-923), trioxifene, keoxifene, LY117018, onapristone, fareston (toremifene citrate), zindoxifene (D-16726), fulvestrant, ARN-810, GW5638, GW7604, ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta), or an analog thereof. In certain embodiments, the nuclear payload comprises a PARP inhibitor.

Also provided is a method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one androgen receptor-targeting epitope to an individual in need thereof. In certain embodiments, the cancer is prostate, breast, triple negative breast cancer, bladder, or liver cancer. In certain embodiments, the androgen receptor-targeting epitope comprises an androgen receptor agonist, a selective androgen-receptor modulator (SARM), an androgen receptor antagonist, a selective estrogen receptor modulator (SERM), an estrogen receptor antagonist, a progestin, or an estrogen. In certain embodiments, the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, darolutamide, or an analog thereof. In certain embodiments, the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, or an analog thereof. In certain embodiments, the nuclear payload comprises a PARP inhibitor.

Also provided is a method of treating or preventing cancer a expressing the estrogen receptor (also known as an estrogen receptor-positive cancer, or ER+ cancer), comprising administering an effective amount of a compound or composition as described herein to an individual in need thereof. In some embodiments, the estrogen receptor-positive cancer is an estrogen receptor overexpressing cancer, or an estrogen receptor overexpressing tumor.

Also provided is a method of treating or preventing cancer a expressing the progesterone receptor (also known as an progesterone receptor-positive cancer, or PR+ cancer), comprising administering an effective amount of a compound or composition as described herein to an individual in need thereof. In some embodiments, the progesterone receptor-positive cancer is an progesterone receptor overexpressing cancer, or an progesterone receptor overexpressing tumor.

Also provided is a method of treating or preventing an estrogen and/or progesterone receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one estrogen and/or progesterone receptor-targeting epitope to an individual in need thereof. In certain embodiments, the cancer is breast, uterine, or ovarian cancer. In certain embodiments, the nuclear payload comprises a PARP inhibitor.

Also provided is a method of treating or preventing cancer a expressing the glucocorticoid receptor (also known as an glucocorticoid receptor-positive cancer, or GR+ cancer), comprising administering an effective amount of a compound or composition as described herein to an individual in need thereof. In some embodiments, the glucocorticoid receptor-positive cancer is an glucocorticoid receptor overexpressing cancer, or an glucocorticoid receptor overexpressing tumor.

Also provided is a method of treating or preventing a glucocorticoid receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one glucocorticoid receptor-targeting epitope to an individual in need thereof. In certain embodiments, the cancer is prostate, breast, uterine, or ovarian cancer. In certain embodiments, the nuclear payload comprises a PARP inhibitor.

Also provided is a method of treating or preventing cancer, comprising administering an effective amount of a compound or composition as described herein, or a pharmaceutically acceptable salt or solvate thereof, in combination with an additional chemotherapeutic agent, to an individual in need thereof.

Also provided is a method for the treatment or prevention of a condition which can be ameliorated by inhibition of PARP in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound or composition of any preceding claim or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

1. Definitions

As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

The term “about” refers to a variation of ±1%, ±3%, ±5%, or ±10% of the value specified. For example, “about 50” can in some embodiments includes a range of from 45 to 55. For integer ranges, the term “about” can include one or two integers greater than and/or less than a recited integer at each end of the range. Unless indicated otherwise herein, the term “about” is intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, the composition, or the embodiment. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more compounds and equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 10 carbon atoms (i.e., C₁₋₁₀ alkyl), 1 to 8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆ alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e. —(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e. —CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includes n-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

“Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (—CHF₂) and trifluoromethyl (—CF₃).

“Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, —NH—, —O—, —S—, —S(O)—, —S(O)₂—, and the like. As used herein, heteroalkyl includes 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Alkoxy” refers to the group “—O-alkyl”.

“Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e., C₂₋₆ alkenyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl), 2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e., C₂₋₆ alkynyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

“Alkoxyalkyl” refers to the group “alkyl-O-alkyl”.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl), or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp³ carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C₃₋₂₀ cycloalkyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10 ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Still further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom.

“Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀ heteroaryl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to 8 carbon ring atoms (i.e., C₃₋₈ heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 5-10 membered ring systems, 5-7 membered ring systems, or 5-6 membered ring systems, each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

“Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more (e.g., 1 to 3) oxo (═O) or N-oxide (—O⁻) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C₂₋₂₀ heterocyclyl), 2 to 12 ring carbon atoms (i.e., C₂₋₁₂ heterocyclyl), 2 to 10 ring carbon atoms (i.e., C₂₋₁₀ heterocyclyl), 2 to 8 ring carbon atoms (i.e., C₂₋₈ heterocyclyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heterocyclyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. The term “heterocyclyl” also includes “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom.

“Alkylene” refers to a divalent alkyl group as defined above. As used herein, alkylene has 1 to 10 carbon atoms (i.e., C₁₋₁₀ alkylene), 1 to 8 carbon atoms (i.e., C₁₋₈ alkylene), 1 to 6 carbon atoms (i.e., C₁₋₆ alkylene), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkylene).

“Heteroalkylene” refers to an alkylene group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group.

The term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, —NH—, —O—, —S—, —S(O)—, —S(O)₂—, and the like. As used herein, heteroalkylene includes 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Alkenylene” refers to an alkylene group containing at least one carbon-carbon double bond and having from 2 to 8 carbon atoms (i.e., C₂₋₈ alkenylene), 2 to 6 carbon atoms (i.e., C₂₋₆ alkenylene), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenylene).

“Heteroalkenylene” refers to a heteroalkylene group containing at least one carbon-carbon double bond and having from 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. The term “heteroalkynyl” also includes those groups having one triple bond and one double bond.

“Alkynylene” refers to an alkylene group containing at least one carbon-carbon triple bond and having from 2 to 8 carbon atoms (i.e., C₂₋₈ alkynylene), 2 to 6 carbon atoms (i.e., C₂₋₆ alkynylene), or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynylene). The term “alkynyl” also includes those groups having one triple bond and one double bond.

“Heteroalkynylene” refers to a heteroalkylene group containing at least one carbon-carbon triple bond and having from 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom. The term “heteroalkynyl” also includes those groups having one triple bond and one double bond.

“Cycloalkylene” refers to a divalent saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkylene” includes cycloalkenylene groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkenylene has from 3 to 10 ring carbon atoms (i.e., C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C₃₋₆ cycloalkyl).

“Heterocycloalkylene” refers to a cycloalkylene group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, —NH—, —O—, —S—, —S(O)—, —S(O)₂—, and the like. As used herein, heterocycloalkylene includes 1 to 9 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

“Oxo” refers to ═O.

“Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur. The term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

“Substituted” as used herein means one or more hydrogen atoms of the group is replaced with a substituent atom or group commonly used in pharmaceutical chemistry. Each substituent can be the same or different. Examples of suitable substituents include, but are not limited to, hydrazide, halo, —CN, —NO₂, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, —OR⁵⁶, —C(O)OR⁵⁶, —C(O)R⁵⁶, —O-alkyl-OR⁵⁶, -alkyl-OR⁵⁶, haloalkyl, haloalkoxy, SR⁵⁶, S(O)R⁵⁶, SO₂R⁵⁶, NR⁵⁶R⁵⁷, —C(O)NR⁵⁶R⁵⁷, NR⁵⁶C(O)R⁵⁷, including seleno and thio derivatives thereof, wherein each R⁵⁶ and R⁵⁷ are independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkyl-alkyl-, heterocyclyl, heterocyclyl-alkyl-, aryl, aryl-alkyl-, heteroaryl, or heteroaryl-alkyl-, and wherein each of the substituents can be optionally further substituted.

Provided are also are stereoisomers, mixture of stereoisomers, tautomers, hydrates, solvates, isotopically enriched analog, and pharmaceutically acceptable salts of the compounds described herein.

The compounds disclosed herein, or their pharmaceutically acceptable salts, may include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another and “diastereomers,” which refers to stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. Thus, all stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates and hydrates of the compounds), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (1) may be atropisomers and are considered as part of this disclosure. Stereoisomers can also be separated by use of chiral HPLC.

Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

The term “hydrate” refers to the complex formed by the combining of a compound described herein and water.

A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine.

Any compound or structure given herein, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. These forms of compounds may also be referred to as an “isotopically enriched analog.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. Such compounds may exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

Certain compounds disclosed herein contain one or more ionizable groups (groups from which a proton can be removed (e.g., —COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)). All possible ionic forms of such molecules and salts thereof are intended to be included individually in the disclosure herein. With regard to salts of the compounds described herein, one of ordinary skill in the art can select from among a wide variety of available counterions those that are appropriate. In specific applications, the selection of a given anion or cation for preparation of a salt may result in increased or decreased solubility of that salt.

As used herein, the term “non-biocleavable linking moiety” is intended to refer to a linking moiety which is not readily hydrolyzed under physiological conditions. As used herein, the term “biocleavable linking moiety” is intended to refer to a linking moiety which is readily hydrolyzed under physiological conditions. In certain embodiments, at least one linking moiety is hydrolyzed under intracellular conditions (e.g., low pH).

As used herein, the term “cancer” refers to a class of diseases of mammals characterized by uncontrolled cellular growth. The term “cancer” is used interchangeably with the terms “tumor,” “solid tumor,” “malignancy,” “hyperproliferation” and “neoplasm.” Cancer includes all types of hyperproliferative growth, hyperplasic growth, neoplastic growth, cancerous growth or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Illustrative examples include, lung, prostate, head and neck, breast and colorectal cancer, melanomas and gliomas (such as a high grade glioma, including glioblastoma multiforme (GBM), the most common and deadliest of malignant primary brain tumors in adult humans).

The phrase “solid tumor” includes, for example, lung cancer, head and neck cancer, brain cancer, oral cancer, colorectal cancer, breast cancer, prostate cancer, pancreatic cancer, and liver cancer. Other types of solid tumors are named for the particular cells that form them, for example, sarcomas formed from connective tissue cells (for example, bone cartilage, fat), carcinomas formed from epithelial tissue cells (for example, breast, colon, pancreas) and lymphomas formed from lymphatic tissue cells (for example, lymph nodes, spleen, thymus). Treatment of all types of solid tumors regardless of naming convention is within the scope of this disclosure.

“Chemotherapeutic agent” refers to any substance capable of reducing or preventing the growth, proliferation, or spread of a cancer cell, a population of cancer cells, tumor, or other malignant tissue. The term is intended also to encompass radiotherapy, or any antitumor or anticancer agent.

As used herein, “treatment” or “treating” is an approach for obtaining a beneficial or desired result, such as a clinical result. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition. In one variation, beneficial or desired clinical results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a cognitive disorder, a psychotic disorder, a neurotransmitter-mediated disorder and/or a neuronal disorder. Preferably, treatment of a disease or condition with a compound of the disclosure or a pharmaceutically acceptable salt thereof is accompanied by no or fewer side effects than are associated with currently available therapies for the disease or condition and/or improves the quality of life of the individual.

The terms “inhibit,” “inhibiting,” and “inhibition” refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.

As used herein, by “combination therapy” is meant a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy comprising a compound detailed herein and anther compound is provided. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or excipients, non-pharmaceutically active compounds, and/or inert substances. In various embodiments, treatment with a combination therapy may result in an additive or even synergistic (e.g., greater than additive) result compared to administration of a single compound of the disclosure alone. In some embodiments, a lower amount of each compound is used as part of a combination therapy compared to the amount generally used for individual therapy. Preferably, the same or greater therapeutic benefit is achieved using a combination therapy than by using any of the individual compounds alone. In some embodiments, the same or greater therapeutic benefit is achieved using a smaller amount (e.g., a lower dose or a less frequent dosing schedule) of a compound in a combination therapy than the amount generally used for individual compound or therapy. Preferably, the use of a small amount of compound results in a reduction in the number, severity, frequency, and/or duration of one or more side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of a compound of the disclosure which in combination with its parameters of efficacy and toxicity, as well as based on the knowledge of the practicing specialist should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

As used herein, the term “agonist” refers to a compound, the presence of which results in a biological activity of a protein that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the protein, such as, for example, PARP.

As used herein, the term “partial agonist” refers to a compound the presence of which results in a biological activity of a protein that is of the same type as that resulting from the presence of a naturally occurring ligand for the protein, but of a lower magnitude.

As used herein, the term “antagonist” or “inhibitor” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a protein. In certain embodiments, the presence of an antagonist or inhibitor results in complete inhibition of a biological activity of a protein, such as, for example, the enzyme poly(ADP-ribose) polymerase (PARP). In certain embodiments, the term “inhibitor” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of an enzyme, such as, for example, the enzyme poly(ADP-ribose) polymerase (PARP). In certain embodiments, the term “antagonist” refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of an enzyme, such as, for example, the enzyme poly(ADP-ribose) polymerase (PARP).

As used herein, the IC₅₀ refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of PARP, in an assay that measures such response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.

The term “cancer,” as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The types of cancer include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary, pancreas or other endocrine organ (thyroid)), prostate, skin (melanoma) or hematological tumors (such as the leukemias).

The term “carrier,” as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid and the like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Further examples of pharmaceutically acceptable salts include those listed in Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977 January; 66(1):1-19. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the disclosure in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are often formed during the process of crystallization. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate.

The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression/encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending/gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression/encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (directly compressible), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending/gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

Compounds

Provided herein are compounds comprising at least one nuclear payload and at least one nuclear receptor-targeting epitope. The compounds described herein are capable of targeting the nucleus of a cell by recognition and binding of a nuclear receptor-targeting epitope to the respective binding site and delivering the nuclear payload to the nucleus of the cell. The nuclear payload then is capable of binding to one or more target sites within the nucleus and/or disrupting one or more cellular processes, causing the cell to die. In certain embodiments, the nuclear payload is bonded to the nuclear receptor-targeting epitope(s) via a linking moiety. In certain embodiments, the linking moiety provides a single or mono-linkage, meaning that the linker is only conjugated to one atom of each of the payload and the epitope.

The compounds described herein can comprise more than one nuclear receptor-targeting epitope. The epitopes can be the same or different, such that the compounds are directed to one or more cellular targets, in addition to the nucleus.

Provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-(L-B)_(m)  I

A-L-(B)_(m)  II

wherein:

A is a nuclear payload;

m is 1, 2 or 3;

each B is independently a nuclear receptor-targeting epitope; and

each L is independently a covalent bond or a linking moiety; provided that at least one L is selected from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L45, and L46, and/or at least one B is selected from B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, and B19:

and further wherein the “*” in L denotes a covalent bond between A and L, and the wavy line in each L and B denotes a covalent bond therebetween.

Provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-(L-B)_(m)  I

A-L-(B)_(m)  II

wherein:

A is a nuclear payload;

m is 1, 2 or 3;

each B is independently a nuclear receptor-targeting epitope; and

each L is independently a covalent bond or a linking moiety; provided that at least one L is selected from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, and L44, and/or at least one B is selected from B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, and B13:

and further wherein the “*” in L denotes a covalent bond between A and L, and the wavy line in each L and B denotes a covalent bond therebetween.

In certain embodiments, the nuclear receptor-targeting epitope of Formula I or II is a nuclear hormone receptor-targeting epitope. In certain embodiments, the nuclear receptor-targeting epitope of Formula I or II is a nuclear steroid receptor-targeting epitope.

Also provided is a compound of Formula I or Formula II, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein each B is independently a nuclear receptor-targeting epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, testosterone, 19-nortestosterone, progesterone, andarine, cortisol, prednisone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta), or an analog thereof.

Also provided is a compound of Formula I, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein A is a nuclear payload which binds to poly(ADP-ribose) polymerase-1 (PARP-1) and/or poly(ADP-ribose) polymerase PARP-2);

m is 1, 2 or 3; and

each B is independently a nuclear receptor-targeting epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof.

Also provided is a compound of Formula II, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein:

A is a nuclear payload which binds to poly(ADP-ribose) polymerase-1 (PARP-1) and/or poly(ADP-ribose) polymerase PARP-2);

m is 1, 2 or 3; and

each B is independently a nuclear receptor-targeting epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof.

In certain embodiments, provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-(L-B)_(m)  I

A-L-(B)_(m)  II

wherein:

A is a nuclear payload;

m is 1, 2 or 3;

each L is independently a covalent bond or a linking moiety; and each B is selected from B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18 and B19:

wherein the wavy line denotes a covalent bond between L and B.

In certain embodiments, provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-(L-B)_(m)  I

A-L-(B)_(m)  II

wherein:

A is a nuclear payload;

m is 1, 2 or 3;

each L is independently a covalent bond or a linking moiety; and each B is selected from B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, and B13:

wherein the wavy line denotes a covalent bond between L and B.

The “linking moiety” of any compounds described herein can be biocleavable (e.g., acid labile) or non-biocleavable. Linking moieties can be linear, branched, saturated, unsaturated, all-carbon or heteroatomic. Linking moieties can also contain one or more rings that are fused, saturated, unsaturated, as well as be all-carbon or heteroatomic. In certain embodiments, the linking moiety is a non-biocleavable linking moiety. In certain embodiments, the linking moiety is a biocleavable linking moiety. In certain embodiments, a nuclear payload is bonded to one nuclear steroid receptor-targeting epitope via a non-biocleavable linking moiety and one or more nuclear steroid receptor-targeting epitope(s) via a biocleavable linking moiety. In certain embodiments, the biocleavable linking moiety is an acid-labile linking moiety. In some embodiments, the linking moiety comprises a hydrazone linkage.

It is contemplated that any linking moiety can be used in the compounds described herein, provided that it does not significantly interfere with or disrupt the desired binding of the nuclear payload or the nuclear receptor-targeting epitope. In some embodiments, the linking moiety is alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, may optionally comprise an arylene, heteroarylene, cycloalkylene or heterocycloalkylene;

and further wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl.

In certain embodiments, the linking moiety is of the formula:

—Y¹—(CH₂)_(n′)—Y²—(CH₂)_(m′)—Y³—

wherein:

each of Y¹, Y², and Y³ are independently a —NR¹¹—, —O—, —S(O)₀₋₂—, —NR¹¹C(O)—, —C(O)NR¹¹—, —NR¹¹S(O)₂—, —S(O)₂NR¹¹—, —CR¹²═N—NR¹¹—, —NR¹¹—N═CR¹²—, —C(O)—, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl;

each R¹¹ is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

each R¹² is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and

n′ and m′ are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

Also provided is a compound of Formula IA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-(Y¹—(CH₂)_(p)—Y²—(CH₂)_(q)—Y³—B)_(r)  IA

wherein:

A is a nuclear payload which binds to poly(ADP-ribose) polymerase-1 (PARP-1) and/or poly(ADP-ribose) polymerase PARP-2);

r is 1, 2 or 3;

each B is independently a nuclear receptor-targeting epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof; and

each of Y¹, Y², and Y³ are independently a bond, —NR¹¹—, —O—, —S(O)₀₋₂—, —NR¹¹C(O)—, —C(O)NR¹¹—, —NR¹¹S(O)₂—, —S(O)₂NR¹¹—, —CR¹²═N—NR¹¹—, —NR¹¹—N═CR¹²—, —C(O)—, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl;

each R¹¹ is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

each R¹² is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and

p and q are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

Also provided is a compound of Formula IIA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-Y¹—(CH₂)_(p)—Y²—(CH₂)_(q)—Y³—(B)_(r)  IIA

wherein:

A is a nuclear payload which binds to poly(ADP-ribose) polymerase-1 (PARP-1) and/or poly(ADP-ribose) polymerase PARP-2);

r is 1, 2 or 3;

each B is independently a nuclear receptor-targeting epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof; and

each of Y¹, Y², and Y³ are independently a bond, —NR¹¹—, —O—, —S(O)₀₋₂—, —NR¹¹C(O)—, —C(O)NR¹¹—, —NR¹¹S(O)₂—, —S(O)₂NR¹¹—, —CR¹²═N—NNR¹¹—, —NR¹¹—, —NR¹¹—N═CR¹²—, —C(O)—, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl;

each R¹¹ is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

each R¹² is independently C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and

p and q are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

In certain embodiments, the linking moiety is not a bond. In certain embodiments, each R¹¹ is independently hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and each R¹² is independently hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.

In certain embodiments, the linking moiety is of the formula:

—Y¹—(CH₂)_(n′)—Y²—(CH₂)_(m′)—Y³—

wherein:

each of Y¹, Y², and Y³ are independently a —NR¹¹—, —O—, —S(O)₀₋₂—, —NR¹¹C(O)—, —C(O)NR¹¹—, —NR¹¹S(O)₂—, —S(O)₂NR¹¹—, —CR¹²═N—NR¹¹—, —NR¹¹—N═CR¹²—, —C(O)—, arylene, heteroarylene, cycloalkylene or heterocycloalkylene; wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene is independently optionally substituted with one to five substituents independently selected from oxo, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄ haloalkyl;

each R¹¹ is independently hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;

each R¹² is independently hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and

n′ and m′ are each independently 0, 1, 2, 3, 4, 5, 6, 7, or 8.

In certain embodiments, the nuclear payload is bonded to the nuclear receptor-targeting epitope via a linking moiety is of the formula:

where the “*” represents a covalent bond to the nuclear payload and the wavy line represents a covalent bond to the nuclear receptor-targeting epitope.

In certain embodiments, the nuclear payload is bonded to the nuclear receptor-targeting epitope via a linking moiety is of the formula:

where the “*” represents a covalent bond to the nuclear payload and the wavy line represents a covalent bond to the nuclear receptor-targeting epitope.

Also provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein each B is independently a nuclear receptor-targeting epitope.

Also provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein each B is independently a nuclear steroid receptor-targeting epitope.

In certain embodiments of any Formula or subformula disclosed herein (e.g., Formula I or II), when m is 1, then the nuclear receptor-targeting epitope is not a peptide, protein, nanoparticle or antibody. In certain embodiments of any Formula or subformula disclosed herein (e.g., Formula I or II), when m is 1, and B is an androgen receptor-targeting epitope, then A is not doxorubicin, or an analog thereof. In certain embodiments of any Formula or subformula disclosed herein (e.g., Formula I or II), when m is 1, and B is an androgen receptor-targeting epitope, then A is not a hydroxamic acid which binds histone deacetylase (HDAC). In certain embodiments of any Formula or subformula disclosed herein (e.g., Formula I or II), when m is 1, and B is an estrogen receptor-targeting epitope, then A is not doxorubicin, or an analog thereof. In certain embodiments of any Formula or subformula disclosed herein (e.g., Formula I or II), when m is 1, and B is an estrogen receptor-targeting epitope, then A is not a hydroxamic acid which binds histone deacetylase (HDAC).

Nuclear Payloads

The nuclear payloads as used herein are generally capable of binding to any site which is involved in a cellular process important for the development of cancer, or cellular replication. In certain embodiments, the nuclear payload binds to the target site within the nucleus and disrupts one or more cellular processes, causing the cell to die. Target sites within the nucleus include, but are not limited to, a sub-nuclear compartment (e.g., promyelocytic leukemia nuclear body (PML NB), nucleolus), a protein-protein interaction within the nucleus (e.g., hypoxia-inducible factor 1α (HIF-1α), FKBP25) or modifications of the chromatin structure. In certain embodiments, the nuclear payload targets a protein involved in the DNA damage repair process, such as, but not limited to, poly(ADP-ribose) polymerase (PARP), DNA-dependent protein kinase (DNA-PK), myelin transcription factor 1 (MYT1), p53, melanocyte-stimulating hormone (MSH), mutL homolog (MLH), ERCC1, apurinic/apyrimidinic endonuclease 1 (APE1), topoisomerase I (Topo I), topoisomerase II (Topo II), Wee1, checkpoint kinase1 (Chk1), checkpoint kinase2 (Chk2), ataxia telangiectasia (ATR), or ataxia-telangiectasia mutated (ATM).

In certain embodiments, the nuclear payload comprises olaparib (AZD-2281), Olaparib TOPARP-A, rucaparib (AG014699, PF-01367338), niraparib, talazoparib (BMN-673), veliparib (ABT-888), CEP 9722, E7016, BGB-290, 3-aminobenzamide, methoxyamine, CC-115, MSC2490484A, AZD6738, VX-970, AZD0156, GDC-0575, MK-8776, LY2606368, AZD1775, belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, topotecan, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide, or an analog thereof. In certain embodiments, the nuclear payload comprises AZD-1775 (MK-1775, Adavosertib), SCH900776 (MK-8776), AZD0156, M6620 (VX-970, VE-822, Berzosertib), AZD6738, or CC-115, or an analog thereof. In certain embodiments, the nuclear payload comprises a combination of CC-115 with an additional nuclear payload. In certain embodiments, the nuclear payload comprises CC-115 and the compound comprises enzalutamide or an analog thereof.

The analogs are derived from the known nuclear payloads named herein and are modified to be conjugated to at least one nuclear receptor-targeting epitope, optionally via a linking moiety. The analogs, even after modification to arrive at the compounds described herein, maintain biological activity, which is comparable to that observed in the original, unmodified nuclear payload. In certain embodiments, the analogs exhibit a binding activity or inhibition which is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of that observed in the original, unmodified nuclear payload.

In certain embodiments, the terms “modified” and “derived from” as used in reference to a nuclear payload, means that at most, one non-hydrogen atom of the original, unmodified nuclear payload (i.e., a known nuclear payload) is replaced by a covalent bond linking at least one nuclear receptor-targeting epitope(s), optionally via a linking moiety. In certain embodiments, the terms “modified” and “derived from” as used in reference to a nuclear payload, means that at most, only one hydrogen atom of the original, unmodified nuclear payload (i.e., a known nuclear payload) is replaced by a covalent bond linking at least one nuclear receptor-targeting epitope(s), optionally via a linking moiety. In certain embodiments, one hydrogen atom bound to a heteroatom (e.g., N, O, or S) of the original, unmodified nuclear payload (i.e., a known nuclear payload) is replaced by a covalent bond linking at least one nuclear receptor-targeting epitope(s), optionally via a linking moiety.

In certain embodiments, the nuclear payload binds to an epigenetic target, such as histone deacetylase (HDAC) (e.g., vorinostat, romidepsin (Istodax), chidamide, panobinostat (Farydak), belinostat (PXD101), panobinostat (LBH589), valproic acid (as Mg valproate), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), SB939, resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), HBI-8000, kevetrin, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215, ME-344, sulforaphane, etc., or an analog thereof), enhancer of zeste homolog 2 (EZH2) (e.g., tazemetostat, MAK638, CPI-1205), DS-3201b, etc., or an analog thereof), histone acetyl transferase (HAT) (e.g., anacardic acid, MG149, C646, etc., or an analog thereof), methyltransferase (e.g., S-adenosyl methionine, etc., or an analog thereof), a bromodomain (e.g., JQ1, I-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010, CPI-203, CPI-0610, olinone, LY294002, or an analog thereof), and the like.

Any known nuclear payload which targets proteins one or more cellular processes can be used as the nuclear payload of the compounds described herein. Small molecule nuclear payloads (i.e., molecular weight of less than about 1,000 g/mol) are contemplated to be especially useful in the compounds described herein (e.g., tripazamine, chetomin, rapamycin, PARP inhibitors, etc.).

In certain embodiments, the compound comprises at least one nuclear payload which binds to poly(ADP-ribose) polymerase (PARP) and are referred to herein as “PARP inhibitors.” PARP inhibitors are cytotoxic agents that prevent such DNA repair leading to the death of cells and tumor growth inhibition. In certain embodiments, the PARP is human PARP, and comprises PARP-1 and/or PARP-2, or a variant thereof. In certain embodiments, the nuclear payload is capable of blocking the enzymatic activity of PARP and/or localizing PARP proteins to sites of DNA damage (i.e., “PARP trapping”). Accordingly, in certain embodiments, the nuclear payload binds to PARP and induces an allosteric conformational change in the enzyme.

In certain embodiments, the nuclear payload binds to the PARP-1 catalytic domain. In certain embodiments, the nuclear payload binds to the PARP-2 catalytic domain. In certain embodiments, the nuclear payload binds to a conserved HYE motif. In certain embodiments, the nuclear payload binds to the nicotinamide-binding pocket in the PARP protein.

In one embodiment, the nuclear payload is an analog of a known PARP inhibitor. Exemplary PARP inhibitors which can be used as nuclear payloads in the compounds described herein include, but are not limited to olaparib (AZD-2281), olaparib TOPARP-A, rucaparib (AG014699, PF-01367338), niraparib, talazoparib (BMN-673), veliparib (ABT-888), CEP 9722, E7016, BGB-290, and 3-aminobenzamide, or an analog thereof.

The PARP inhibitor analogs are derived from PARP inhibitors and are modified to be conjugated to at least one nuclear steroid receptor-targeting epitope, optionally via a linking moiety. The PARP inhibitor analogs, even after modification to arrive at the compounds described herein, maintain biological activity which is comparable to that observed in the original, unmodified PARP inhibitor. In certain embodiments, the PARP inhibitor analogs maintain the ability to inhibit PARP. In certain embodiments, the PARP inhibitor analogs exhibit a binding activity which is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of that observed in the original, unmodified PARP inhibitor. In certain embodiments, the compound as described herein is binds to a poly(ADP-ribose) polymerase (PARP) (e.g., PARP-1 and/or PARP-2) with an IC₅₀ of less than about 500 nM, or less than about 400 nM, or less than about 350 nM, or less than about 300 nM, or less than about 200 nM, or less than about 100 nM, or less than about 50 nM.

In certain embodiments, the nuclear payload (e.g., PARP inhibitor analog) comprises one or more moieties capable of having a binding interaction with G863, Y907, S904, A898, K903, E988, Y896, and/or Y889 of PARP-1. In certain embodiments, the nuclear payload (e.g., PARP inhibitor analog) comprises one or more moieties capable of having a binding interaction with Y889, Y896, H862, G863, S904, Y907, K903, E988, and/or M890 of PARP-1. In certain embodiments, the nuclear payload (e.g., PARP inhibitor analog) comprises one or more moieties capable of having a binding interaction with Y896, Q763, G863, 5904, Y907, K903, and/or E988 of PARP-1. In certain embodiments, the nuclear payload (e.g., PARP inhibitor analog) comprises one or more positively charged moieties (e.g., amino group) which interact with the side chains of Q763, D766, and/or Y896 of PARP-1. In certain embodiments, the nuclear payload (e.g., PARP inhibitor analog) comprises one or more moieties capable of having a binding interaction with E322, D326, I425, S417, H415, E545, and/or Y449 of PARP-2.

In certain embodiments, the nuclear payload comprises rucaparib (AG014699, PF-01367338), or an analog thereof (i.e., rucaparib-containing analogs). Accordingly, provided is a compound of Formula III, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

each of R¹, R², R³ and R⁴ is independently -L-(B)_(m), hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵, —C(═O)NR⁵R⁶, —NR⁵C(═O) R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂NR⁵R⁶, —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R², R³ and R⁴ are independently optionally substituted with one or more R¹⁰ as valency permits;

m is 1, 2, or 3;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R10 is independently halo, cyano, nitro, —OR⁷, —SR⁷, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂ NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino; and

each R7 and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

provided that at least one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, only one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, provided is a compound of Formula IIIA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

each of R¹, R², R³ and R⁴ is independently -L-(B)_(m), hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵, —C(═O)NR⁵R⁶, —NR⁵C(═O) R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂NR⁵R⁶, —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R², R³ and R⁴ are independently optionally substituted with one or more R¹⁰ as valency permits;

m is 1, 2, or 3;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R¹⁰ is independently halo, cyano, nitro, —OR⁷, —SR⁷, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino; and

each R⁷ and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

provided that at least one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, provided is a compound of Formula IIIB, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

R² is -L-(B)_(m);

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments of Formula III, IIIA and IIIB, the nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope. In certain embodiments of Formula III, IIIA and IIIB, m is 1. In certain embodiments of Formula III, IIIA and IIIB, m is 2. In certain embodiments of Formula III and MA, only one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, the nuclear payload is derived from talazoparib (BMN-673), or an analog thereof (i.e., talazoparib-containing analogs). Accordingly, provided is a compound of Formula IV, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

each of R¹, R², R³ and R⁴ is independently -L-(B)_(m), hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵, —C(═O)NR⁵R⁶, —NR⁵C(═O) R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂NR⁵R⁶, —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R², R³ and R⁴ are independently optionally substituted with one or more R¹⁰ as valency permits;

m is 1, 2, or 3;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R¹⁰ is independently halo, cyano, nitro, —OR⁷, —SR⁷, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino; and

each R⁷ and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

provided that at least one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, provided is a compound of Formula IVA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

R² is -L-(B)_(m);

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments, provided is a compound of Formula IVB, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

R²¹ and R²³ are each independently selected from hydrogen, halo, hydroxyl, C₁₋₁₂ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₁₂ alkoxy, C₁₋₁₂ alkoxyalkyl; wherein each alkyl, cycloalkyl, alkoxy, alkoxyalkyl are independently optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, nitro, C₁₋₁₂ alkyl, and C₃₋₁₀ cycloalkyl, wherein R²³ is not hydroxyl;

R²² and R²⁴ are each independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, —C(═O)R⁵⁰, —C(═O)OR⁵⁰, —C(═O)N(R⁵⁰)₂, —S(═O)₀₋₂R⁵⁰, —S(═O)₁₋₂N(R⁵⁰)₂, —NR⁵⁰S(═O)₁₋₂R⁵⁰, C₃₋₁₀ cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, aryl, heterocyclyl, or heteroaryl may be independently optionally substituted with 1, 2, or 3 R²⁹;

R²⁰ and R²⁵ are each independently selected from the group consisting of hydrogen, C₁₋₁₂ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₁₂ alkoxyalkyl, C₁₋₁₂ haloalkyl, C₁₋₁₂ alkyl-OH and C₁₋₁₂ alkyl-NR⁵¹R⁵²;

R²⁶, R²⁷, and R²⁸ are each independently selected from the group consisting of hydrogen, halo, cyano, nitro, amino, hydroxyl, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy, C₃₋₁₀ cycloalkyl, —C(═O)-alkyl, —C(═O)-alkoxy, haloalkoxy, haloalkyl, heteroalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo, hydroxyl, or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits;

each R²⁹ is selected from hydroxyl, halo, cyano, nitro, —OR⁵¹, —SR⁵¹, —SF₅, —NR⁵¹R⁵², C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵¹, —C(═O)OR⁵¹, —OC(═O)OR⁵¹, —OC(═O)R⁵¹, —C(═O)NR⁵¹R⁵², —OC(═O)NR⁵¹R⁵², —NR⁵¹C(═O)NR⁵¹R⁵², —S(═O)₁₋₂R⁵¹, —S(═O)₁₋₂ NR⁵¹R⁵², —NR⁵¹S(═O)₁₋₂R⁵², —NR⁵¹S(═O)₁₋₂NR⁵¹R⁵², —NR⁵¹C(═O)R⁵², —NR⁵¹C(═O)OR⁵² or —C═NOR⁵¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R²⁹ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits;

each R⁵⁰ is independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R⁵⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵¹ and R⁵² is independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R⁵¹ and R⁵² are optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵¹ and R⁵² are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

provided at least one R²² or R²⁴ comprises a -L-(B)_(m) group bonded thereto, wherein each L is independently a covalent bond or a linking moiety, each B is independently a nuclear receptor-targeting epitope, and m is 1, 2 or 3.

In the compounds of Formula VIB, at least one R²² or R²⁴ comprises a substituent having a -L-(B)_(m) group bonded thereto. As such, it should be understood that the -L-(B)_(m) group is not bound directly to the tricyclic core.

In certain embodiments of Formula IV, IVA and IVB the nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope. In certain embodiments of Formula IV, IVA and IVB, m is 1. In certain embodiments of Formula IV, IVA and IVB, m is 2. In certain embodiments of Formula IV, only one of R¹, R², R³ and R4 is -L-(B)_(m).

In certain embodiments, the nuclear payload is derived from olaparib (AZD-2281), or an analog thereof (i.e., olaparib-containing analogs). In certain embodiments, the compound is of Formula V, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

each R¹, R², R³ and R⁴ is independently -L-(B)_(m), hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵, —C(═O)NR⁵R⁶, —NR⁵C(═O) R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂NR⁵R⁶, —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R², R³ and R⁴ are independently optionally substituted with one or more R¹⁰ as valency permits;

m is 1, 2, or 3;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R¹⁰ is independently halo, cyano, nitro, —OR¹, —SR¹, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

each R⁷ and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

R⁹ is hydrogen or R²; and

provided that at least one R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, provided is a compound of Formula VA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

each of R¹, R², R³ and R⁴ is independently -L-(B)_(m), hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵, —C(═O)NR⁵R⁶, —NR⁵C(═O) R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂ NR⁵R⁶, —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R², R³ and R⁴ are independently optionally substituted with one or more R¹⁰ as valency permits;

m is 1, 2, or 3;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R¹⁰ is independently halo, cyano, nitro, —OR⁷, —SR⁷, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂ NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂ NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino; and

each R⁷ and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

provided that at least one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, provided is a compound of Formula VB, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

R² is -L-(B)_(m);

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments, provided is a compound of Formula VC, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

A and B together represent an optionally substituted, fused aromatic ring:

R³⁰ and R³¹ are independently hydrogen or C₁₋₁₂ alkyl, or when X is —CR³³R³⁴, R³⁰, R³¹, R³³ and R³⁴ together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring;

R³² is hydrogen or halo;

X is —NR³³ or —CR³³R³⁴; where if X is —NR³³ then t is 1 or 2; and if X is —CR³³R³⁴ then t is 1;

R³³ is hydrogen, optionally substituted C₁₋₁₂ alkyl, aryl, heterocyclyl, —C(═O)R⁵⁰, —C(═O)OR⁵⁰, —C(═O)OR⁵⁰, —C(═O)N(R⁵⁰)₂, —S(═O)₀₋₂R⁵⁰, —S(═O)₁₋₂N(R⁵⁰)₂, —NR⁵⁰S(═O)₁₋₂R⁵⁰;

R³⁴ is hydrogen, hydroxyl, or amino;

or R³³ and R³⁴ may together form a C₃₋₁₀ cycloalkyl or heterocyclyl group; and

each R⁵⁰ is independently hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R⁵⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits;

provided at least one R³⁰, R³¹, R³³ or R³⁴ group comprises a -L-(B)_(m) group bonded thereto, wherein each L is independently a covalent bond or a linking moiety, each B is independently a nuclear receptor-targeting epitope, and m is 1, 2 or 3.

In certain embodiments, the compound is of Formula VD, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

each R¹, R², R³ and R⁴ is independently -L-(B)_(m), hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵, —C(═O)NR⁵R⁶, —NR⁵C(═O) R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂ NR⁵R⁶, —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R², R³ and R⁴ are independently optionally substituted with one or more R¹⁰ as valency permits;

m is 1, 2, or 3;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R¹⁰ is independently halo, cyano, nitro, —OR⁷, —SR⁷, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂ NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂ NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits;

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

each R⁷ and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino; and

provided that at least one R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, the compound is of Formula VE, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

R² is -L-(B)_(m);

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments of Formula V, VA, VB, VC, VD, and VE, the nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope. In certain embodiments of Formula V, VA, VB, VC, VD, and VE, m is 1. In certain embodiments of Formula V, VA, VB, VC, VD, and VE, m is 2. In certain embodiments of Formula V, VA, VC, and VD, only one of R¹, R², R³ and R⁴ is -L-(B)_(m). In certain embodiments of Formula V and VA, only one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, the nuclear payload is derived from veliparib (ABT-888), or an analog thereof (i.e., veliparib-containing analogs). Also provided is a compound of Formula VI, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

-   -   each of R¹, R², R³ and R⁴ is independently -L-(B)_(m), hydrogen,         C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl,         heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵,         —C(═O)NR⁵R⁶, —NR⁵C(═O) R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂ NR⁵R⁶,         —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl,         cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R², R³ and         R⁴ are independently optionally substituted with one or more R¹⁰         as valency permits;

m is 1, 2, or 3;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R¹⁰ is independently halo, cyano, nitro, —OR⁷, —SR⁷, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂ NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂ NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino; and

each R⁷ and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

provided that at least one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, provided is a compound of Formula VIA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

R² is -L-(B)_(m);

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments of Formula VI and VIA, the nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope. In certain embodiments of Formula VI and VIA, m is 1. In certain embodiments of Formula VI and VIA, m is 2. In certain embodiments of Formula V, only one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments, the nuclear payload comprises CC-115 or an analog thereof (CC-115-containing analogs). Also provided is a compound of Formula VII or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

each of R¹, R² and R³ are independently -L-(B)_(m), hydrogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁵, —C(═O)OR⁵, —OC(═O)R⁵, —C(═O)NR⁵R⁶, —NR⁵C(═O)R⁶, —S(═O)₁₋₂R⁵, —S(═O)₁₋₂ NR⁵R⁶, —NR⁵S(═O)₁₋₂R⁶ or —C═NOR⁵, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹, R² and R³ are independently optionally substituted with one or more R¹⁰ as valency permits;

each L is independently a covalent bond or a linking moiety;

each B is independently a nuclear receptor-targeting epitope;

each R¹⁰ is independently halo, cyano, nitro, —OR⁷, —SR⁷, —SF₅, —NR⁷R⁸, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₀ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(═O)R⁷, —C(═O)OR⁷, —OC(═O)OR⁷, —OC(═O)R⁷, —C(═O)NR⁷R⁸, —OC(═O)NR⁷R⁸, —NR⁷C(═O)NR⁷R⁸, —S(═O)₁₋₂R⁷, —S(═O)₁₋₂ NR⁷R⁸, —NR⁷S(═O)₁₋₂R⁸, —NR⁷S(═O)₁₋₂ NR⁷R⁸, —NR⁷C(═O)R⁸, —NR⁷C(═O)OR⁸ or —C═NOR⁷, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl of R¹⁰ are independently optionally substituted with one or more halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino as valency permits; and

each R⁵ and R⁶ is independently hydrogen, deuterium, C₁₋₁₂ alkyl or C₃₋₁₂ cycloalkyl, optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino; and

each R⁷ and R⁸ is independently hydrogen, deuterium or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁷ and R⁸ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino;

provided that at least one of R¹, R² and R³ is -L-(B)_(m).

In certain embodiments, provided is a compound of Formula VIIA, or stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

wherein:

R² is -L-(B)_(m);

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments of Formula VII and VIIA, the nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope. In certain embodiments of Formula VII and VIIA, m is 1. In certain embodiments of Formula VII and VIIA, m is 2. In certain embodiments of Formula VII, only one of R¹, R², R³ and R⁴ is -L-(B)_(m).

In certain embodiments of a Formula disclosed herein, each R⁵ and R⁶ is independently hydrogen, deuterium, or C₁₋₁₂ alkyl optionally substituted with oxo, halo, hydroxyl or amino as valency permits; or R⁵ and R⁶ are taken together with the atoms to which they are attached to form heterocyclyl optionally substituted by halo or C₁₋₁₂ alkyl optionally substituted by oxo, halo, hydroxyl or amino.

In certain embodiments, the nuclear payload binds DNA-dependent protein kinase (DNA-PK). In certain embodiments, the nuclear payload is an inhibitor of DNA-dependent protein kinase (DNA-PK). In certain embodiments, the nuclear payload is derived from AZD-1775 (MK-1775, Adavosertib), SCH900776 (MK-8776), AZD0156, M6620 (VX-970, VE-822, Berzosertib), AZD6738, or CC-115, or an analog thereof. In certain embodiments, provided is a compound of formula:

wherein one hydrogen atom is replaced by -L-(B)_(m); wherein

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments, the hydrogen atom replaced by -L-(B)_(m), is on a heteroatom. In certain embodiments, the hydrogen atom replaced by -L-(B)_(m), is on a nitrogen. In certain embodiments, the hydrogen atom replaced by -L-(B)_(m) is on an oxygen. In certain embodiments, the hydrogen atom replaced by -L-(B)_(m), is on a carbon. In certain embodiments, the nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope. In certain embodiments, m is 1. In certain embodiments, m is 2.

In certain embodiments, provided is a compound of Formula:

wherein:

R² is -L-(B)_(m);

m is 1, 2, or 3;

L is a covalent bond or a linking moiety; and

each B is independently a nuclear receptor-targeting epitope.

In certain embodiments of any compound, Formula or embodiment disclosed herein, the nuclear receptor-targeting epitope is a nuclear steroid receptor-targeting epitope. In certain embodiments, m is 1. In certain embodiments, m is 2.

Nuclear Receptor-Targeting Epitopes

Provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-(L-B)_(m)  I

A-(L-B)_(m)  II

wherein:

A is a nuclear payload;

m is 1, 2 or 3;

each B is independently a nuclear receptor-targeting epitope; and

each L is independently selected from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L46 and L46:

wherein the “*” in L denotes a covalent bond between A and L, and the wavy line in each L denotes a covalent bond between L and B.

Provided is a compound of Formula I or II, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof:

A-L(L-B)_(m)  I

A-L-(B)_(m)  II

wherein:

A is a nuclear payload;

m is 1, 2 or 3;

each B is independently a nuclear receptor-targeting epitope; and

each L is independently selected from L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, and L44:

wherein the “*” in L denotes a covalent bond between A and L, and the wavy line in each L denotes a covalent bond between L and B.

As used herein, “nuclear receptor-targeting epitope” refers to the portion of the compound described herein (e.g., the “B” moiety of Formula I or Formula II) which portion is derived from a nuclear targeting agent as disclosed herein and interacts with a ligand-binding domain of the target nuclear receptor, i.e., the portion of the compound which drives a ligand-binding interaction. The nuclear receptor-targeting epitope serves to associate the compound with a target nuclear receptor, e.g. a nuclear steroid receptor, facilitate the localization of compound to nuclear steroid receptor-expressing cells, and translocate the nuclear payload from the cytosol to nucleus, allowing the compound to accumulate in the nucleus. The level of accumulation can be controlled by selecting the appropriate nuclear receptor-targeting epitope. For example, the compounds described herein can accumulate in the nucleus to varying degrees, high in the case of a full agonist (e.g., dihydrotestosterone (DHT)), moderate in the case of a partial agonist (e.g., bicalutamide), and low, in the case of antagonists (e.g., enzalutamide), through nuclear translocation of the nuclear steroid receptor which happens, following epitope binding to the receptor.

The steroid receptor target can be any steroid receptor, including, but not limited to, those which are over-expressed on cancer cells. In certain embodiments, at least one nuclear steroid receptor-targeting epitope is capable of binding to a ligand binding domain of a nuclear steroid receptor, such as a ligand binding domain on an estrogen receptor, glucocorticoid receptor, progesterone receptor or androgen receptor.

Exemplary nuclear steroid receptor-targeting epitopes include those derived from an androgen receptor agonist, an androgen receptor antagonist, a selective androgen-receptor modulator (SARM), an estrogen receptor agonist, an estrogen receptor antagonist, a selective estrogen receptor modulator (SERM), a glucocorticoid receptor antagonist, a glucocorticoid receptor agonist, a selective glucocorticoid receptor modulator (SGRM), a progesterone receptor antagonist, a progesterone receptor agonist, a selective progesterone receptor modulator (SPRM), or a combination thereof. The nuclear steroid receptor-targeting epitopes are typically capable of binding to a nuclear steroid receptor with an IC₅₀ of less than about 500 nM, or less than about 400 nM, or less than about 300 nM, or less than about 200 nM, or less than about 100 nM, or with an EC₅₀ of less than about 1 μM, or less than about 900 nM, or less than about 800 nM, or less than about 700 nM, or less than about 600 nM, or less than about 500 nM, or less than about 400 nM, or less than about 3400 nM, or less than about 200 nM, or less than about 100 nM.

In certain embodiments, the nuclear steroid receptor-targeting epitope is an agonist at the androgen receptor. In certain embodiments, the nuclear steroid receptor-targeting epitope is an antagonist at the androgen receptor.

In certain embodiments, the nuclear steroid receptor-targeting epitope is steroidal (e.g., dihydrotestosterone). In certain embodiments, the nuclear steroid receptor-targeting epitope is non-steroidal (e.g., enzalutamide, apalutamide and bicalutamide).

The analogs are derived from the known nuclear steroid receptor-targeting epitope described herein and are modified to be conjugated to at least one nuclear steroid payload, optionally via a linking moiety. The analogs, even after modification to arrive at the compounds described herein, maintain biological activity, which is comparable to that observed in the original, unmodified nuclear steroid receptor-targeting epitope. In certain embodiments, the analogs exhibit a binding activity or inhibition which is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of that observed in the original, unmodified nuclear steroid receptor-targeting epitope.

In certain embodiments, the analogs are derived from a known nuclear receptor-targeting epitope, such as a known nuclear steroid receptor-targeting epitope. In certain embodiments, the term “derived from” as used in reference to a nuclear receptor-targeting epitope, means that at most, one non-hydrogen atom of an original, unmodified nuclear receptor-targeting compound (i.e., a known nuclear steroid receptor-targeting compound) is replaced by a covalent bond to the nuclear payload, optionally via a linking moiety. Exemplary non-hydrogen atoms include, but are not limited to, —CH₃, —OH, ═O, and —NH₂. In certain embodiments, the term “derived from” as used in reference to a nuclear receptor-targeting epitope, means that at most, one non-hydrogen atom of an original, unmodified nuclear receptor-targeting compound (i.e., a known nuclear steroid receptor-targeting compound) is replaced by a covalent bond to the nuclear payload, optionally via a linking moiety. In certain embodiments, one hydrogen atom bound to a heteroatom (e.g., N, O, or S) of the original, unmodified nuclear receptor-targeting compound (i.e., a known nuclear steroid receptor-targeting compound) is replaced by a covalent bond to the nuclear payload, optionally via a linking moiety.

In certain embodiments, the nuclear steroid receptor-targeting epitope is an androgen receptor-targeting epitope. As used herein, the term “androgen receptor-targeting epitope” is intended to refer to the portion of the compound which binds to an androgen receptor agonist or androgen receptor antagonist (including partial androgen receptor agonists or partial androgen receptor antagonists) and which is capable of shuttling a compound from the cytoplasm into the nucleus of a cell. The “androgen receptor” (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that, when activated by binding an androgen receptor binder (e.g., an androgenic hormone such as testosterone, or dihydrotestosterone) in the cytoplasm, is capable of translocating the androgenic hormone into the nucleus.

Exemplary androgen receptor-targeting epitopes which can be used in the compounds described herein include, but are not limited to, an androgen receptor agonist, a selective androgen-receptor modulator (SARM) (e.g., enobosarm), an androgen receptor antagonist (e.g., bicalutamide, flutamide, nilutamide, or enzalutamide), a selective estrogen receptor modulator (SERM) (e.g., tamoxifen, toremifene, or raloxifene), an estrogen receptor antagonist (e.g., fulvestrant), a progestin (e.g., megestrol acetate), an estrogen (e.g., estramustine), ketoconazole, abiraterone, darolutamide, or an analog thereof.

In certain embodiments, the nuclear steroid receptor-targeting epitope is a selective androgen receptor modulator (SARM). In certain embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from testosterone, a testosterone ester (e.g., testosterone enanthate, propionate, cypionate, etc., or an analog thereof), enobosarm, BMS-564929, PS178990, LGD-4033 (ligandrol), LGD-2941, AC-262,356, JNJ-28330835, JNJ-37654032, JNJ-26146900, LGD-2226, LGD-3303, LGD-121071, LG-120907, S-40503, 5-23, RAD-140, acetothiolutamide, andarine (S-4), LG-121071, TFM-4AS-1, YK-11, MK-0773 (PF-05314882), GSK2849466, GSK2881078, GSK8698, GSK4336, ACP-105, TT701, LY2452473, 1-(2-hydroxy-2-methyl-3-phenoxypropanoyl)-indoline-4-carbonitrile-derivatives (J Med Chem. 2014, 57(6), 2462-71), or an analog thereof.

In certain embodiments, a single atom on the nuclear receptor-targeting epitope as disclosed herein is replaced for attachment to the remainder of the compound (e.g., the moiety A-L- of Formula I and Formula II). In certain embodiments, a halogen atom on a nuclear receptor-targeting epitope disclosed herein is replaced for attachment to the remainder of the compound. In certain embodiments, a hydrogen atom on a nuclear receptor-targeting epitope disclosed herein is replaced for attachment to the remainder of the compound. In certain embodiments, the hydrogen atom is on a heteroatom. In certain embodiments, the hydrogen atom is on a nitrogen. In certain embodiments, the hydrogen atom is on an oxygen. In certain embodiments, the hydrogen atom is on a carbon.

In certain embodiments, the moiety —B of Formula I or Formula II comprises at least one nuclear receptor-targeting epitope derived from:

or a stereoisomer or a mixture of stereoisomers thereof or an analog thereof.

These and other selective androgen receptor modulator (SARMs) which can be used as a nuclear steroid receptor-targeting epitope in the compounds described herein can be found in U.S. Pat. Nos. 6,462,038, 6,777,427, WO2001/027086, WO2004/013104, WO2004/000816, WO2004/0113309, US2006/0211756, US2006/0063819, US2005/245485, US2005/250741, US2005/277681, WO2006/060108, WO2004/041277, WO2003/034987, U52006/0148893, U52006/0142387, WO2005/000795, WO2005/085185, WO2006/133216, WO2006/044707, WO2006/124447, WO2007/002181, WO2005/108351, WO2005/115361, and US2006/0160845.

In certain embodiments, the nuclear steroid receptor-targeting epitope is a selective estrogen receptor modulator (SERM). In certain embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from anordrin, bazedoxifene, broparestrol (Acnestrol), clomifene (Clomid), cyclofenil (Sexovid), lasofoxifene (Fablyn), ormeloxifene (Centron, Novex, Novex-DS, Sevista), ospemifene (Osphena, deaminohydroxytoremifene), raloxifene (Evista), tamoxifen (Nolvadex), toremifene (Fareston; 4-chlorotamoxifen), acolbifene, afimoxifene (4-hydroxytamoxifen; metabolite of tamoxifen), elacestrant, enclomifene ((E)-clomifene), endoxifen (4-hydroxy-N-desmethyltamoxifen; metabolite of tamoxifen), zuclomifene ((Z)-clomifene), bazedoifene, arzoxifene, brilanestrant, clomifenoxide (clomiphene N-oxide; metabolite of clomifene), droloxifene (3-hydroxytamoxifen), etacstil, fispemifene, GW-7604 (4-hydroxyetacstil), idoxifene (pyrrolidino-4-iodotamoxifen), levormeloxifene ((L)-ormeloxifene), miproxifene, nafoxidine, nitromifene (CI-628), panomifene, pipendoxifene (ERA-923), trioxifene, keoxifene, LY117018, onapristone, fareston (toremifene citrate) or zindoxifene (D-16726), or an analog thereof.

In certain embodiments, the SERM is classified structurally as a triphenylethylene (tamoxifen, clomifene, toremifene, droloxifene, idoxifene, ospemifene, fispemifene, afimoxifene, etc., or an analog thereof), a benzothiophene (raloxifene, arzoxifene, etc., or an analog thereof), an indole (bazedoxifene, zindoxifene, pipendoxifene, etc., or an analog thereof), a tetrahydronaphthalene (lasofoxifene, nafoxidine, etc., or an analog thereof), or a benzopyran (acolbifene, ormeloxifene, levormeloxifene, etc., or an analog thereof).

In certain embodiments, the nuclear steroid receptor-targeting epitope is a selective estrogen receptor downregulator (SERD). In certain embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from fulvestrant, ARN-810, GW5638, or GW7604.

In certain embodiments, the nuclear steroid receptor-targeting epitope is a selective progesterone receptor modulator (SPRM). In certain embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from ulipristal acetate, asoprisnil (J867), mifepristone, telapristone (CDB-4124, Proellex, Progenta), or an analog thereof.

In certain embodiments, the compound comprises at least one nuclear steroid receptor-targeting epitope independently comprises an epitope derived from estrogen, estetrol, estriol, estrone, progesterone, enobosarm, bicalutamide, apalutamide, testosterone, dihydrotestosterone, estradiol, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, bazedoxifene, ospemifene, megestrol acetate, estramustine, abiraterone, LGD-2941, BMS-564929, ostarine, or an analog thereof.

In certain embodiments, at least one nuclear steroid receptor-targeting epitope is an androgen receptor-targeting epitope, and comprises:

or a stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the linking moiety or nuclear payload. In certain embodiments, at least one nuclear steroid receptor-targeting epitope is an androgen receptor-targeting epitope, and comprises:

or a stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the linking moiety or nuclear payload.

In certain embodiments, at least one nuclear steroid receptor-targeting epitope is an estrogen receptor-targeting epitope, and comprises:

or a stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the linking moiety or nuclear payload.

In certain embodiments, at least one nuclear steroid receptor-targeting epitope (i.e., B) of a compound disclosed herein, is:

or a stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the linking moiety or nuclear payload. In certain embodiments, at least one nuclear steroid receptor-targeting epitope (i.e., B) of a compound disclosed herein, is:

or a stereoisomer or a mixture of stereoisomers thereof or an analog thereof, where the wavy line indicates the point of attachment to the linking moiety or nuclear payload.

In certain embodiments, the nuclear steroid receptor-targeting epitope is not, or does not contain, a peptide, protein, nanoparticle or antibody.

In certain embodiments, provided is a compound of Formula A-L-B, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein:

A is A1, A2, A3, or A4, as shown in Table 2:

TABLE 2 A1

A2

A3

A4

L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L45, or L46, as shown in Table 3:

TABLE 3 L1

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

L12

L13

L14

L15

L16

L17

L18

L19

L20

L21

L22

L23

L24

L25

L26

L27

L28

L29

L30

L31

L32

L33

L34

L35

L36

L37

L38

L39

L40

L41

L42

L43

L44

L45

L46

and;

B is B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, or B19 as shown in Table 4:

TABLE 4 B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

and further wherein the “*” in each A and L moiety denotes a covalent bond therebetween, and the wavy line in each L and B denotes a covalent bond therebetween.

In certain embodiments, provided is a compound of Formula A-L-B, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein:

A is A1, A2, or A3, as shown in Table 2:

TABLE 2 A1

A2

A3

L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L45, or L46, as shown in Table 3:

TABLE 3 L1

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

L12

L13

L14

L15

L16

L17

L18

L19

L20

L21

L22

L23

L24

L25

L26

L27

L28

L29

L30

L31

L32

L33

L34

L35

L36

L37

L38

L39

L40

L41

L42

L43

L44

L45

L46

and;

B is B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, or B19 as shown in Table 4:

TABLE 4 B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

and further wherein the “*” in each A and L moiety denotes a covalent bond therebetween, and the wavy line in each L and B denotes a covalent bond therebetween.

In certain embodiments, A is A1, A2 or A3. In certain embodiments, B is B14, B15, B16, B16, B17, B18, or B19. In certain embodiments, L is L45 or L46. In certain embodiments, when A is A4, then L is L45 or L46. In certain embodiments, when A is A4, then B is B14, B15, B16, B16, B17, B18, or B19. In certain embodiments, L is L45 or L46 and B is B14, B15, B16, B16, B17, B18, or B19. In certain embodiments, when A is A4, then L is L45 or L46 and B is B14, B15, B16, B16, B17, B18, or B19.

In certain embodiments, provided is a compound of Formula A-L-B as described in Table 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, wherein:

A is A1, A2, A3, or A4, as shown in Table 2:

TABLE 2 A1

A2

A3

A4

L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L45, or L46, as shown in Table 3:

TABLE 3 L1

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

L12

L13

L14

L15

L16

L17

L18

L19

L20

L21

L22

L23

L24

L25

L26

L27

L28

L29

L30

L31

L32

L33

L34

L35

L36

L37

L38

L39

L40

L41

L42

L43

L44

L45

L46

and;

B is B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, or B19 as shown in Table 4:

TABLE 4 B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

B17

B18

B19

and further wherein the “*” in each A and L moiety denotes a covalent bond therebetween, and the wavy line in each L and B denotes a covalent bond therebetween.

TABLE 1 No. A-L-B 1 A1-L1-B1 2 A1-L1-B2 3 A1-L1-B3 4 A1-L1-B4 5 A1-L1-B5 6 A1-L1-B6 7 A1-L1-B7 8 A1-L1-B8 9 A1-L1-B9 10 A1-L1-B10 11 A1-L1-B11 12 A1-L1-B12 13 A1-L1-B13 14 A1-L2-B1 15 A1-L2-B2 16 A1-L2-B3 17 A1-L2-B4 18 A1-L2-B5 19 A1-L2-B6 20 A1-L2-B7 21 A1-L2-B8 22 A1-L2-B9 23 A1-L2-B10 24 A1-L2-B11 25 A1-L2-B12 26 A1-L2-B13 27 A1-L3-B1 28 A1-L3-B2 29 A1-L3-B3 30 A1-L3-B4 31 A1-L3-B5 32 A1-L3-B6 33 A1-L3-B7 34 A1-L3-B8 35 A1-L3-B9 36 A1-L3-B10 37 A1-L3-B11 38 A1-L3-B12 39 A1-L3-B13 40 A1-L4-B1 41 A1-L4-B2 42 A1-L4-B3 43 A1-L4-B4 44 A1-L4-B5 45 A1-L4-B6 46 A1-L4-B7 47 A1-L4-B8 48 A1-L4-B9 49 A1-L4-B10 50 A1-L4-B11 51 A1-L4-B12 52 A1-L4-B13 53 A1-L5-B1 54 A1-L5-B2 55 A1-L5-B3 56 A1-L5-B4 57 A1-L5-B5 58 A1-L5-B6 59 A1-L5-B7 60 A1-L5-B8 61 A1-L5-B9 62 A1-L5-B10 63 A1-L5-B11 64 A1-L5-B12 65 A1-L5-B13 66 A1-L6-B1 67 A1-L6-B2 68 A1-L6-B3 69 A1-L6-B4 70 A1-L6-B5 71 A1-L6-B6 72 A1-L6-B7 73 A1-L6-B8 74 A1-L6-B9 75 A1-L6-B10 76 A1-L6-B11 77 A1-L6-B12 78 A1-L6-B13 79 A1-L7-B1 80 A1-L7-B2 81 A1-L7-B3 82 A1-L7-B4 83 A1-L7-B5 84 A1-L7-B6 85 A1-L7-B7 86 A1-L7-B8 87 A1-L7-B9 88 A1-L7-B10 89 A1-L7-B11 90 A1-L7-B12 91 A1-L7-B13 92 A1-L8-B1 93 A1-L8-B2 94 A1-L8-B3 95 A1-L8-B4 96 A1-L8-B5 97 A1-L8-B6 98 A1-L8-B7 99 A1-L8-B8 100 A1-L8-B9 101 A1-L8-B10 102 A1-L8-B11 103 A1-L8-B12 104 A1-L8-B13 105 A1-L9-B1 106 A1-L9-B2 107 A1-L9-B3 108 A1-L9-B7 109 A1-L9-B8 110 A1-L9-B9 111 A1-L9-B11 112 A1-L9-B13 113 A1-L20-B1 114 A1-L20-B2 115 A1-L20-B3 116 A1-L20-B4 117 A1-L20-B5 118 A1-L20-B6 119 A1-L20-B7 120 A1-L20-B8 121 A1-L20-B9 122 A1-L20-B10 123 A1-L20-B11 124 A1-L20-B12 125 A1-L20-B13 126 A1-L21-B1 127 A1-L21-B2 128 A1-L21-B3 129 A1-L21-B4 130 A1-L21-B5 131 A1-L21-B6 132 A1-L21-B7 133 A1-L21-B8 134 A1-L21-B9 135 A1-L21-B10 136 A1-L21-B11 137 A1-L21-B12 138 A1-L21-B13 139 A1-L22-B1 140 A1-L22-B2 141 A1-L22-B3 142 A1-L22-B4 143 A1-L22-B5 144 A1-L22-B6 145 A1-L22-B7 146 A1-L22-B8 147 A1-L22-B9 148 A1-L22-B10 149 A1-L22-B11 150 A1-L22-B12 151 A1-L22-B13 152 A1-L23-B1 153 A1-L23-B2 154 A1-L23-B3 155 A1-L23-B4 156 A1-L23-B5 157 A1-L23-B6 158 A1-L23-B7 159 A1-L23-B8 160 A1-L23-B9 161 A1-L23-B10 162 A1-L23-B11 163 A1-L23-B12 164 A1-L23-B13 165 A1-L24-B1 166 A1-L24-B2 167 A1-L24-B3 168 A1-L24-B4 169 A1-L24-B5 170 A1-L24-B6 171 A1-L24-B7 172 A1-L24-B8 173 A1-L24-B9 174 A1-L24-B10 175 A1-L24-B11 176 A1-L24-B12 177 A1-L24-B13 178 A1-L30-B1 179 A1-L30-B2 180 A1-L30-B3 181 A1-L30-B4 182 A1-L30-B5 183 A1-L30-B6 184 A1-L30-B7 185 A1-L30-B8 186 A1-L30-B9 187 A1-L30-B10 188 A1-L30-B11 189 A1-L30-B12 190 A1-L30-B13 191 A1-L31-B1 192 A1-L31-B2 193 A1-L31-B3 194 A1-L31-B4 195 A1-L31-B5 196 A1-L31-B6 197 A1-L31-B7 198 A1-L31-B8 199 A1-L31-B9 200 A1-L31-B10 201 A1-L31-B11 202 A1-L31-B12 203 A1-L31-B13 204 A1-L32-B1 205 A1-L32-B2 206 A1-L32-B3 207 A1-L32-B7 208 A1-L32-B8 209 A1-L32-B9 210 A1-L32-B11 211 A1-L32-B13 212 A1-L39-B1 213 A1-L39-B2 214 A1-L39-B3 215 A1-L39-B4 216 A1-L39-B5 217 A1-L39-B6 218 A1-L39-B7 219 A1-L39-B8 220 A1-L39-B9 221 A1-L39-B10 222 A1-L39-B11 223 A1-L39-B12 224 A1-L39-B13 225 A1-L40-B1 226 A1-L40-B2 227 A1-L40-B3 228 A1-L40-B4 229 A1-L40-B5 230 A1-L40-B6 231 A1-L40-B7 232 A1-L40-B8 233 A1-L40-B9 234 A1-L40-B10 235 A1-L40-B11 236 A1-L40-B12 237 A1-L40-B13 238 A1-L41-B1 239 A1-L41-B2 240 A1-L41-B3 241 A1-L41-B4 242 A1-L41-B5 243 A1-L41-B6 244 A1-L41-B7 245 A1-L41-B8 246 A1-L41-B9 247 A1-L41-B10 248 A1-L41-B11 249 A1-L41-B12 250 A1-L41-B13 251 A1-L42-B1 252 A1-L42-B2 253 A1-L42-B3 254 A1-L42-B4 255 A1-L42-B5 256 A1-L42-B6 257 A1-L42-B7 258 A1-L42-B8 259 A1-L42-B9 260 A1-L42-B10 261 A1-L42-B11 262 A1-L42-B12 263 A1-L42-B13 264 A1-L43-B1 265 A1-L43-B2 266 A1-L43-B3 267 A1-L43-B4 268 A1-L43-B5 269 A1-L43-B6 270 A1-L43-B7 271 A1-L43-B8 272 A1-L43-B9 273 A1-L43-B10 274 A1-L43-B11 275 A1-L43-B12 276 A1-L43-B13 277 A1-L44-B1 278 A1-L44-B2 279 A1-L44-B3 280 A1-L44-B7 281 A1-L44-B8 282 A1-L44-B9 283 A1-L44-B11 284 A1-L44-B13 285 A2-L1-B1 286 A2-L1-B2 287 A2-L1-B3 288 A2-L1-B4 289 A2-L1-B5 290 A2-L1-B6 291 A2-L1-B7 292 A2-L1-B8 293 A2-L1-B9 294 A2-L1-B10 295 A2-L1-B11 296 A2-L1-B12 297 A2-L1-B13 298 A2-L2-B1 299 A2-L2-B2 300 A2-L2-B3 301 A2-L2-B4 302 A2-L2-B5 303 A2-L2-B6 304 A2-L2-B7 305 A2-L2-B8 306 A2-L2-B9 307 A2-L2-B10 308 A2-L2-B11 309 A2-L2-B12 310 A2-L2-B13 311 A2-L3-B1 312 A2-L3-B2 313 A2-L3-B3 314 A2-L3-B4 315 A2-L3-B5 316 A2-L3-B6 317 A2-L3-B7 318 A2-L3-B8 319 A2-L3-B9 320 A2-L3-B10 321 A2-L3-B11 322 A2-L3-B12 323 A2-L3-B13 324 A2-L4-B1 325 A2-L4-B2 326 A2-L4-B3 327 A2-L4-B4 328 A2-L4-B5 329 A2-L4-B6 330 A2-L4-B7 331 A2-L4-B8 332 A2-L4-B9 333 A2-L4-B10 334 A2-L4-B11 335 A2-L4-B12 336 A2-L4-B13 337 A2-L5-B1 338 A2-L5-B2 339 A2-L5-B3 340 A2-L5-B4 341 A2-L5-B5 342 A2-L5-B6 343 A2-L5-B7 344 A2-L5-B8 345 A2-L5-B9 346 A2-L5-B10 347 A2-L5-B11 348 A2-L5-B12 349 A2-L5-B13 350 A2-L6-B1 351 A2-L6-B2 352 A2-L6-B3 353 A2-L6-B4 354 A2-L6-B5 355 A2-L6-B6 356 A2-L6-B7 357 A2-L6-B8 358 A2-L6-B9 359 A2-L6-B10 360 A2-L6-B11 361 A2-L6-B12 362 A2-L6-B13 363 A2-L7-B1 364 A2-L7-B2 365 A2-L7-B3 366 A2-L7-B4 367 A2-L7-B5 368 A2-L7-B6 369 A2-L7-B7 370 A2-L7-B8 371 A2-L7-B9 372 A2-L7-B10 373 A2-L7-B11 374 A2-L7-B12 375 A2-L7-B13 376 A2-L8-B1 377 A2-L8-B2 378 A2-L8-B3 379 A2-L8-B4 380 A2-L8-B5 381 A2-L8-B6 382 A2-L8-B7 383 A2-L8-B8 384 A2-L8-B9 385 A2-L8-B10 386 A2-L8-B11 387 A2-L8-B12 388 A2-L8-B13 389 A2-L9-B1 390 A2-L9-B2 391 A2-L9-B3 392 A2-L9-B7 393 A2-L9-B8 394 A2-L9-B9 395 A2-L9-B11 396 A2-L9-B13 397 A2-L10-B1 398 A2-L10-B2 399 A2-L10-B3 400 A2-L10-B4 401 A2-L10-B5 402 A2-L10-B6 403 A2-L10-B7 404 A2-L10-B8 405 A2-L10-B9 406 A2-L10-B10 407 A2-L10-B11 408 A2-L10-B12 409 A2-L10-B13 410 A2-L11-B1 411 A2-L11-B2 412 A2-L11-B3 413 A2-L11-B4 414 A2-L11-B5 415 A2-L11-B6 416 A2-L11-B7 417 A2-L11-B8 418 A2-L11-B9 419 A2-L11-B10 420 A2-L11-B11 421 A2-L11-B12 422 A2-L11-B13 423 A2-L12-B1 424 A2-L12-B2 425 A2-L12-B3 426 A2-L12-B7 427 A2-L12-B8 428 A2-L12-B9 429 A2-L12-B11 430 A2-L12-B13 431 A2-L13-B1 432 A2-L13-B2 433 A2-L13-B3 434 A2-L13-B4 435 A2-L13-B5 436 A2-L13-B6 437 A2-L13-B7 438 A2-L13-B8 439 A2-L13-B9 440 A2-L13-B10 441 A2-L13-B11 442 A2-L13-B12 443 A2-L13-B13 444 A2-L14-B1 445 A2-L14-B2 446 A2-L14-B3 447 A2-L14-B4 448 A2-L14-B5 449 A2-L14-B6 450 A2-L14-B7 451 A2-L14-B8 452 A2-L14-B9 453 A2-L14-B10 454 A2-L14-B11 455 A2-L14-B12 456 A2-L14-B13 457 A2-L15-B1 458 A2-L15-B2 459 A2-L15-B3 460 A2-L15-B4 461 A2-L15-B5 462 A2-L15-B6 463 A2-L15-B7 464 A2-L15-B8 465 A2-L15-B9 466 A2-L15-B10 467 A2-L15-B11 468 A2-L15-B12 469 A2-L15-B13 470 A2-L16-B1 471 A2-L16-B2 472 A2-L16-B3 473 A2-L16-B4 474 A2-L16-B5 475 A2-L16-B6 476 A2-L16-B7 477 A2-L16-B8 478 A2-L16-B9 479 A2-L16-B10 480 A2-L16-B11 481 A2-L16-B12 482 A2-L16-B13 483 A2-L17-B1 484 A2-L17-B2 485 A2-L17-B3 486 A2-L17-B7 487 A2-L17-B8 488 A2-L17-B9 489 A2-L17-B11 490 A2-L17-B13 491 A2-L18-B1 492 A2-L18-B2 493 A2-L18-B3 494 A2-L18-B4 495 A2-L18-B5 496 A2-L18-B6 497 A2-L18-B7 498 A2-L18-B8 499 A2-L18-B9 500 A2-L18-B10 501 A2-L18-B11 502 A2-L18-B12 503 A2-L18-B13 504 A2-L19-B1 505 A2-L19-B2 506 A2-L19-B3 507 A2-L19-B4 508 A2-L19-B5 509 A2-L19-B6 510 A2-L19-B7 511 A2-L19-B8 512 A2-L19-B9 513 A2-L19-B10 514 A2-L19-B11 515 A2-L19-B12 516 A2-L19-B13 517 A2-L20-B1 518 A2-L20-B2 519 A2-L20-B3 520 A2-L20-B4 521 A2-L20-B5 522 A2-L20-B6 523 A2-L20-B7 524 A2-L20-B8 525 A2-L20-B9 526 A2-L20-B10 527 A2-L20-B11 528 A2-L20-B12 529 A2-L20-B13 530 A2-L21-B1 531 A2-L21-B2 532 A2-L21-B3 533 A2-L21-B4 534 A2-L21-B5 535 A2-L21-B6 536 A2-L21-B7 537 A2-L21-B8 538 A2-L21-B9 539 A2-L21-B10 540 A2-L21-B11 541 A2-L21-B12 542 A2-L21-B13 543 A2-L22-B1 544 A2-L22-B2 545 A2-L22-B3 546 A2-L22-B4 547 A2-L22-B5 548 A2-L22-B6 549 A2-L22-B7 550 A2-L22-B8 551 A2-L22-B9 552 A2-L22-B10 553 A2-L22-B11 554 A2-L22-B12 555 A2-L22-B13 556 A2-L23-B1 557 A2-L23-B2 558 A2-L23-B3 559 A2-L23-B4 560 A2-L23-B5 561 A2-L23-B6 562 A2-L23-B7 563 A2-L23-B8 564 A2-L23-B9 565 A2-L23-B10 566 A2-L23-B11 567 A2-L23-B12 568 A2-L23-B13 569 A2-L24-B1 570 A2-L24-B2 571 A2-L24-B3 572 A2-L24-B4 573 A2-L24-B5 574 A2-L24-B6 575 A2-L24-B7 576 A2-L24-B8 577 A2-L24-B9 578 A2-L24-B10 579 A2-L24-B11 580 A2-L24-B12 581 A2-L24-B13 582 A2-L25-B1 583 A2-L25-B2 584 A2-L25-B3 585 A2-L25-B4 586 A2-L25-B5 587 A2-L25-B6 588 A2-L25-B7 589 A2-L25-B8 590 A2-L25-B9 591 A2-L25-B10 592 A2-L25-B11 593 A2-L25-B12 594 A2-L25-B13 595 A2-L26-B1 596 A2-L26-B2 597 A2-L26-B3 598 A2-L26-B4 599 A2-L26-B5 600 A2-L26-B6 601 A2-L26-B7 602 A2-L26-B8 603 A2-L26-B9 604 A2-L26-B10 605 A2-L26-B11 606 A2-L26-B12 607 A2-L26-B13 608 A2-L27-B1 609 A2-L27-B2 610 A2-L27-B3 611 A2-L27-B4 612 A2-L27-B5 613 A2-L27-B6 614 A2-L27-B7 615 A2-L27-B8 616 A2-L27-B9 617 A2-L27-B10 618 A2-L27-B11 619 A2-L27-B12 620 A2-L27-B13 621 A2-L28-B1 622 A2-L28-B2 623 A2-L28-B3 624 A2-L28-B4 625 A2-L28-B5 626 A2-L28-B6 627 A2-L28-B7 628 A2-L28-B8 629 A2-L28-B9 630 A2-L28-B10 631 A2-L28-B11 632 A2-L28-B12 633 A2-L28-B13 634 A2-L29-B1 635 A2-L29-B2 636 A2-L29-B3 637 A2-L29-B4 638 A2-L29-B5 639 A2-L29-B6 640 A2-L29-B7 641 A2-L29-B8 642 A2-L29-B9 643 A2-L29-B10 644 A2-L29-B11 645 A2-L29-B12 646 A2-L29-B13 647 A2-L30-B1 648 A2-L30-B2 649 A2-L30-B3 650 A2-L30-B4 651 A2-L30-B5 652 A2-L30-B6 653 A2-L30-B7 654 A2-L30-B8 655 A2-L30-B9 656 A2-L30-B10 657 A2-L30-B11 658 A2-L30-B12 659 A2-L30-B13 660 A2-L31-B1 661 A2-L31-B2 662 A2-L31-B3 663 A2-L31-B4 664 A2-L31-B5 665 A2-L31-B6 666 A2-L31-B7 667 A2-L31-B8 668 A2-L31-B9 669 A2-L31-B10 670 A2-L31-B11 671 A2-L31-B12 672 A2-L31-B13 673 A2-L32-B1 674 A2-L32-B2 675 A2-L32-B3 676 A2-L32-B7 677 A2-L32-B8 678 A2-L32-B9 679 A2-L32-B11 680 A2-L32-B13 681 A2-L33-B1 682 A2-L33-B2 683 A2-L33-B3 684 A2-L33-B4 685 A2-L33-B5 686 A2-L33-B6 687 A2-L33-B7 688 A2-L33-B8 689 A2-L33-B9 690 A2-L33-B10 691 A2-L33-B11 692 A2-L33-B12 693 A2-L33-B13 694 A2-L34-B1 695 A2-L34-B2 696 A2-L34-B3 697 A2-L34-B7 698 A2-L34-B8 699 A2-L34-B9 700 A2-L34-B11 701 A2-L34-B13 702 A2-L35-B1 703 A2-L35-B2 704 A2-L35-B3 705 A2-L35-B4 706 A2-L35-B5 707 A2-L35-B6 708 A2-L35-B7 709 A2-L35-B8 710 A2-L35-B9 711 A2-L35-B10 712 A2-L35-B11 713 A2-L35-B12 714 A2-L35-B13 715 A2-L36-B1 716 A2-L36-B2 717 A2-L36-B3 718 A2-L36-B4 719 A2-L36-B5 720 A2-L36-B6 721 A2-L36-B7 722 A2-L36-B8 723 A2-L36-B9 724 A2-L36-B10 725 A2-L36-B11 726 A2-L36-B12 727 A2-L36-B13 728 A2-L37-B1 729 A2-L37-B2 730 A2-L37-B3 731 A2-L37-B4 732 A2-L37-B5 733 A2-L37-B6 734 A2-L37-B7 735 A2-L37-B8 736 A2-L37-B9 737 A2-L37-B10 738 A2-L37-B11 739 A2-L37-B12 740 A2-L37-B13 741 A2-L38-B1 742 A2-L38-B2 743 A2-L38-B3 744 A2-L38-B4 745 A2-L38-B5 746 A2-L38-B6 747 A2-L38-B7 748 A2-L38-B8 749 A2-L38-B9 750 A2-L38-B10 751 A2-L38-B11 752 A2-L38-B12 753 A2-L38-B13 754 A2-L39-B1 755 A2-L39-B2 756 A2-L39-B3 757 A2-L39-B4 758 A2-L39-B5 759 A2-L39-B6 760 A2-L39-B7 761 A2-L39-B8 762 A2-L39-B9 763 A2-L39-B10 764 A2-L39-B11 765 A2-L39-B12 766 A2-L39-B13 767 A2-L40-B1 768 A2-L40-B2 769 A2-L40-B3 770 A2-L40-B4 771 A2-L40-B5 772 A2-L40-B6 773 A2-L40-B7 774 A2-L40-B8 775 A2-L40-B9 776 A2-L40-B10 777 A2-L40-B11 778 A2-L40-B12 779 A2-L40-B13 780 A2-L41-B1 781 A2-L41-B2 782 A2-L41-B3 783 A2-L41-B4 784 A2-L41-B5 785 A2-L41-B6 786 A2-L41-B7 787 A2-L41-B8 788 A2-L41-B9 789 A2-L41-B10 790 A2-L41-B11 791 A2-L41-B12 792 A2-L41-B13 793 A2-L42-B1 794 A2-L42-B2 795 A2-L42-B3 796 A2-L42-B4 797 A2-L42-B5 798 A2-L42-B6 799 A2-L42-B7 800 A2-L42-B8 801 A2-L42-B9 802 A2-L42-B10 803 A2-L42-B11 804 A2-L42-B12 805 A2-L42-B13 806 A2-L43-B1 807 A2-L43-B2 808 A2-L43-B3 809 A2-L43-B4 810 A2-L43-B5 811 A2-L43-B6 812 A2-L43-B7 813 A2-L43-B8 814 A2-L43-B9 815 A2-L43-B10 816 A2-L43-B11 817 A2-L43-B12 818 A2-L43-B13 819 A2-L44-B1 820 A2-L44-B2 821 A2-L44-B3 822 A2-L44-B7 823 A2-L44-B8 824 A2-L44-B9 825 A2-L44-B11 826 A2-L44-B13 827 A3-L1-B1 828 A3-L1-B2 829 A3-L1-B3 830 A3-L1-B4 831 A3-L1-B5 832 A3-L1-B6 833 A3-L1-B7 834 A3-L1-B8 835 A3-L1-B9 836 A3-L1-B10 837 A3-L1-B11 838 A3-L1-B12 839 A3-L1-B13 840 A3-L2-B1 841 A3-L2-B2 842 A3-L2-B3 843 A3-L2-B4 844 A3-L2-B5 845 A3-L2-B6 846 A3-L2-B7 847 A3-L2-B8 848 A3-L2-B9 849 A3-L2-B10 850 A3-L2-B11 851 A3-L2-B12 852 A3-L2-B13 853 A3-L3-B1 854 A3-L3-B2 855 A3-L3-B3 856 A3-L3-B4 857 A3-L3-B5 858 A3-L3-B6 859 A3-L3-B7 860 A3-L3-B8 861 A3-L3-B9 862 A3-L3-B10 863 A3-L3-B11 864 A3-L3-B12 865 A3-L3-B13 866 A3-L4-B1 867 A3-L4-B2 868 A3-L4-B3 869 A3-L4-B4 870 A3-L4-B5 871 A3-L4-B6 872 A3-L4-B7 873 A3-L4-B8 874 A3-L4-B9 875 A3-L4-B10 876 A3-L4-B11 877 A3-L4-B12 878 A3-L4-B13 879 A3-L5-B1 880 A3-L5-B2 881 A3-L5-B3 882 A3-L5-B4 883 A3-L5-B5 884 A3-L5-B6 885 A3-L5-B7 886 A3-L5-B8 887 A3-L5-B9 888 A3-L5-B10 889 A3-L5-B11 890 A3-L5-B12 891 A3-L5-B13 892 A3-L6-B1 893 A3-L6-B2 894 A3-L6-B3 895 A3-L6-B4 896 A3-L6-B5 897 A3-L6-B6 898 A3-L6-B7 899 A3-L6-B8 900 A3-L6-B9 901 A3-L6-B10 902 A3-L6-B11 903 A3-L6-B12 904 A3-L6-B13 905 A3-L7-B1 906 A3-L7-B2 907 A3-L7-B3 908 A3-L7-B4 909 A3-L7-B5 910 A3-L7-B6 911 A3-L7-B7 912 A3-L7-B8 913 A3-L7-B9 914 A3-L7-B10 915 A3-L7-B11 916 A3-L7-B12 917 A3-L7-B13 918 A3-L8-B1 919 A3-L8-B2 920 A3-L8-B3 921 A3-L8-B4 922 A3-L8-B5 923 A3-L8-B6 924 A3-L8-B7 925 A3-L8-B8 926 A3-L8-B9 927 A3-L8-B10 928 A3-L8-B11 929 A3-L8-B12 930 A3-L8-B13 931 A3-L9-B1 932 A3-L9-B2 933 A3-L9-B3 934 A3-L9-B7 935 A3-L9-B8 936 A3-L9-B9 937 A3-L9-B11 938 A3-L9-B13 939 A3-L10-B1 940 A3-L10-B2 941 A3-L10-B3 942 A3-L10-B4 943 A3-L10-B5 944 A3-L10-B6 945 A3-L10-B7 946 A3-L10-B8 947 A3-L10-B9 948 A3-L10-B10 949 A3-L10-B11 950 A3-L10-B12 951 A3-L10-B13 952 A3-L11-B1 953 A3-L11-B2 954 A3-L11-B3 955 A3-L11-B4 956 A3-L11-B5 957 A3-L11-B6 958 A3-L11-B7 959 A3-L11-B8 960 A3-L11-B9 961 A3-L11-B10 962 A3-L11-B11 963 A3-L11-B12 964 A3-L11-B13 965 A3-L12-B1 966 A3-L12-B2 967 A3-L12-B3 968 A3-L12-B7 969 A3-L12-B8 970 A3-L12-B9 971 A3-L12-B11 972 A3-L12-B13 973 A3-L13-B1 974 A3-L13-B2 975 A3-L13-B3 976 A3-L13-B4 977 A3-L13-B5 978 A3-L13-B6 979 A3-L13-B7 980 A3-L13-B8 981 A3-L13-B9 982 A3-L13-B10 983 A3-L13-B11 984 A3-L13-B12 985 A3-L13-B13 986 A3-L14-B1 987 A3-L14-B2 988 A3-L14-B3 989 A3-L14-B4 990 A3-L14-B5 991 A3-L14-B6 992 A3-L14-B7 993 A3-L14-B8 994 A3-L14-B9 995 A3-L14-B10 996 A3-L14-B11 997 A3-L14-B12 998 A3-L14-B13 999 A3-L15-B1 1000 A3-L15-B2 1001 A3-L15-B3 1002 A3-L15-B4 1003 A3-L15-B5 1004 A3-L15-B6 1005 A3-L15-B7 1006 A3-L15-B8 1007 A3-L15-B9 1008 A3-L15-B10 1009 A3-L15-B11 1010 A3-L15-B12 1011 A3-L15-B13 1012 A3-L16-B1 1013 A3-L16-B2 1014 A3-L16-B3 1015 A3-L16-B4 1016 A3-L16-B5 1017 A3-L16-B6 1018 A3-L16-B7 1019 A3-L16-B8 1020 A3-L16-B9 1021 A3-L16-B10 1022 A3-L16-B11 1023 A3-L16-B12 1024 A3-L16-B13 1025 A3-L17-B1 1026 A3-L17-B2 1027 A3-L17-B3 1028 A3-L17-B7 1029 A3-L17-B8 1030 A3-L17-B9 1031 A3-L17-B11 1032 A3-L17-B13 1033 A3-L18-B1 1034 A3-L18-B2 1035 A3-L18-B3 1036 A3-L18-B4 1037 A3-L18-B5 1038 A3-L18-B6 1039 A3-L18-B7 1040 A3-L18-B8 1041 A3-L18-B9 1042 A3-L18-B10 1043 A3-L18-B11 1044 A3-L18-B12 1045 A3-L18-B13 1046 A3-L19-B1 1047 A3-L19-B2 1048 A3-L19-B3 1049 A3-L19-B4 1050 A3-L19-B5 1051 A3-L19-B6 1052 A3-L19-B7 1053 A3-L19-B8 1054 A3-L19-B9 1055 A3-L19-B10 1056 A3-L19-B11 1057 A3-L19-B12 1058 A3-L19-B13 1059 A3-L20-B1 1060 A3-L20-B2 1061 A3-L20-B3 1062 A3-L20-B4 1063 A3-L20-B5 1064 A3-L20-B6 1065 A3-L20-B7 1066 A3-L20-B8 1067 A3-L20-B9 1068 A3-L20-B10 1069 A3-L20-B11 1070 A3-L20-B12 1071 A3-L20-B13 1072 A3-L21-B1 1073 A3-L21-B2 1074 A3-L21-B3 1075 A3-L21-B4 1076 A3-L21-B5 1077 A3-L21-B6 1078 A3-L21-B7 1079 A3-L21-B8 1080 A3-L21-B9 1081 A3-L21-B10 1082 A3-L21-B11 1083 A3-L21-B12 1084 A3-L21-B13 1085 A3-L22-B1 1086 A3-L22-B2 1087 A3-L22-B3 1088 A3-L22-B4 1089 A3-L22-B5 1090 A3-L22-B6 1091 A3-L22-B7 1092 A3-L22-B8 1093 A3-L22-B9 1094 A3-L22-B10 1095 A3-L22-B11 1096 A3-L22-B12 1097 A3-L22-B13 1098 A3-L23-B1 1099 A3-L23-B2 1100 A3-L23-B3 1101 A3-L23-B4 1102 A3-L23-B5 1103 A3-L23-B6 1104 A3-L23-B7 1105 A3-L23-B8 1106 A3-L23-B9 1107 A3-L23-B10 1108 A3-L23-B11 1109 A3-L23-B12 1110 A3-L23-B13 1111 A3-L24-B1 1112 A3-L24-B2 1113 A3-L24-B3 1114 A3-L24-B4 1115 A3-L24-B5 1116 A3-L24-B6 1117 A3-L24-B7 1118 A3-L24-B8 1119 A3-L24-B9 1120 A3-L24-B10 1121 A3-L24-B11 1122 A3-L24-B12 1123 A3-L24-B13 1124 A3-L25-B1 1125 A3-L25-B2 1126 A3-L25-B3 1127 A3-L25-B4 1128 A3-L25-B5 1129 A3-L25-B6 1130 A3-L25-B7 1131 A3-L25-B8 1132 A3-L25-B9 1133 A3-L25-B10 1134 A3-L25-B11 1135 A3-L25-B12 1136 A3-L25-B13 1137 A3-L26-B1 1138 A3-L26-B2 1139 A3-L26-B3 1140 A3-L26-B4 1141 A3-L26-B5 1142 A3-L26-B6 1143 A3-L26-B7 1144 A3-L26-B8 1145 A3-L26-B9 1146 A3-L26-B10 1147 A3-L26-B11 1148 A3-L26-B12 1149 A3-L26-B13 1150 A3-L27-B1 1151 A3-L27-B2 1152 A3-L27-B3 1153 A3-L27-B4 1154 A3-L27-B5 1155 A3-L27-B6 1156 A3-L27-B7 1157 A3-L27-B8 1158 A3-L27-B9 1159 A3-L27-B10 1160 A3-L27-B11 1161 A3-L27-B12 1162 A3-L27-B13 1163 A3-L28-B1 1164 A3-L28-B2 1165 A3-L28-B3 1166 A3-L28-B4 1167 A3-L28-B5 1168 A3-L28-B6 1169 A3-L28-B7 1170 A3-L28-B8 1171 A3-L28-B9 1172 A3-L28-B10 1173 A3-L28-B11 1174 A3-L28-B12 1175 A3-L28-B13 1176 A3-L29-B1 1177 A3-L29-B2 1178 A3-L29-B3 1179 A3-L29-B4 1180 A3-L29-B5 1181 A3-L29-B6 1182 A3-L29-B7 1183 A3-L29-B8 1184 A3-L29-B9 1185 A3-L29-B10 1186 A3-L29-B11 1187 A3-L29-B12 1188 A3-L29-B13 1189 A3-L30-B1 1190 A3-L30-B2 1191 A3-L30-B3 1192 A3-L30-B4 1193 A3-L30-B5 1194 A3-L30-B6 1195 A3-L30-B7 1196 A3-L30-B8 1197 A3-L30-B9 1198 A3-L30-B10 1199 A3-L30-B11 1200 A3-L30-B12 1201 A3-L30-B13 1202 A3-L31-B1 1203 A3-L31-B2 1204 A3-L31-B3 1205 A3-L31-B4 1206 A3-L31-B5 1207 A3-L31-B6 1208 A3-L31-B7 1209 A3-L31-B8 1210 A3-L31-B9 1211 A3-L31-B10 1212 A3-L31-B11 1213 A3-L31-B12 1214 A3-L31-B13 1215 A3-L32-B1 1216 A3-L32-B2 1217 A3-L32-B3 1218 A3-L32-B7 1219 A3-L32-B8 1220 A3-L32-B9 1221 A3-L32-B11 1222 A3-L32-B13 1223 A3-L33-B1 1224 A3-L33-B2 1225 A3-L33-B3 1226 A3-L33-B4 1227 A3-L33-B5 1228 A3-L33-B6 1229 A3-L33-B7 1230 A3-L33-B8 1231 A3-L33-B9 1232 A3-L33-B10 1233 A3-L33-B11 1234 A3-L33-B12 1235 A3-L33-B13 1236 A3-L34-B1 1237 A3-L34-B2 1238 A3-L34-B3 1239 A3-L34-B7 1240 A3-L34-B8 1241 A3-L34-B9 1242 A3-L34-B11 1243 A3-L34-B13 1244 A3-L35-B1 1245 A3-L35-B2 1246 A3-L35-B3 1247 A3-L35-B4 1248 A3-L35-B5 1249 A3-L35-B6 1250 A3-L35-B7 1251 A3-L35-B8 1252 A3-L35-B9 1253 A3-L35-B10 1254 A3-L35-B11 1255 A3-L35-B12 1256 A3-L35-B13 1257 A3-L36-B1 1258 A3-L36-B2 1259 A3-L36-B3 1260 A3-L36-B4 1261 A3-L36-B5 1262 A3-L36-B6 1263 A3-L36-B7 1264 A3-L36-B8 1265 A3-L36-B9 1266 A3-L36-B10 1267 A3-L36-B11 1268 A3-L36-B12 1269 A3-L36-B13 1270 A3-L37-B1 1271 A3-L37-B2 1272 A3-L37-B3 1273 A3-L37-B4 1274 A3-L37-B5 1275 A3-L37-B6 1276 A3-L37-B7 1277 A3-L37-B8 1278 A3-L37-B9 1279 A3-L37-B10 1280 A3-L37-B11 1281 A3-L37-B12 1282 A3-L37-B13 1283 A3-L38-B1 1284 A3-L38-B2 1285 A3-L38-B3 1286 A3-L38-B4 1287 A3-L38-B5 1288 A3-L38-B6 1289 A3-L38-B7 1290 A3-L38-B8 1291 A3-L38-B9 1292 A3-L38-B10 1293 A3-L38-B11 1294 A3-L38-B12 1295 A3-L38-B13 1296 A3-L39-B1 1297 A3-L39-B2 1298 A3-L39-B3 1299 A3-L39-B4 1300 A3-L39-B5 1301 A3-L39-B6 1302 A3-L39-B7 1303 A3-L39-B8 1304 A3-L39-B9 1305 A3-L39-B10 1306 A3-L39-B11 1307 A3-L39-B12 1308 A3-L39-B13 1309 A3-L40-B1 1310 A3-L40-B2 1311 A3-L40-B3 1312 A3-L40-B4 1313 A3-L40-B5 1314 A3-L40-B6 1315 A3-L40-B7 1316 A3-L40-B8 1317 A3-L40-B9 1318 A3-L40-B10 1319 A3-L40-B11 1320 A3-L40-B12 1321 A3-L40-B13 1322 A3-L41-B1 1323 A3-L41-B2 1324 A3-L41-B3 1325 A3-L41-B4 1326 A3-L41-B5 1327 A3-L41-B6 1328 A3-L41-B7 1329 A3-L41-B8 1330 A3-L41-B9 1331 A3-L41-B10 1332 A3-L41-B11 1333 A3-L41-B12 1334 A3-L41-B13 1335 A3-L42-B1 1336 A3-L42-B2 1337 A3-L42-B3 1338 A3-L42-B4 1339 A3-L42-B5 1340 A3-L42-B6 1341 A3-L42-B7 1342 A3-L42-B8 1343 A3-L42-B9 1344 A3-L42-B10 1345 A3-L42-B11 1346 A3-L42-B12 1347 A3-L42-B13 1348 A3-L43-B1 1349 A3-L43-B2 1350 A3-L43-B3 1351 A3-L43-B4 1352 A3-L43-B5 1353 A3-L43-B6 1354 A3-L43-B7 1355 A3-L43-B8 1356 A3-L43-B9 1357 A3-L43-B10 1358 A3-L43-B11 1359 A3-L43-B12 1360 A3-L43-B13 1361 A3-L44-B1 1362 A3-L44-B2 1363 A3-L44-B3 1364 A3-L44-B7 1365 A3-L44-B8 1366 A3-L44-B9 1367 A3-L44-B11 1368 A3-L44-B13 1369 A1-L20-B14 1370 A1-L21-B14 1371 A1-L22-B14 1372 A1-L23-B14 1373 A1-L24-B14 1374 A1-L2-B14 1375 A1-L3-B14 1376 A1-L45-B14 1377 A1-L20-B15 1378 A1-L21-B15 1379 A1-L22-B15 1380 A1-L23-B15 1381 A1-L24-B15 1382 A1-L2-B15 1383 A1-L3-B15 1384 A1-L45-B15 1385 A1-L20-B16 1386 A1-L21-B16 1387 A1-L22-B16 1388 A1-L23-B16 1389 A1-L24-B16 1390 A1-L2-B16 1391 A1-L3-B16 1392 A1-L45-B16 1393 A1-L20-B17 1394 A1-L21-B17 1395 A1-L22-B17 1396 A1-L23-B17 1397 A1-L24-B17 1398 A1-L2-B17 1399 A1-L3-B17 1400 A1-L45-B17 1401 A1-L20-B18 1402 A1-L21-B18 1403 A1-L22-B18 1404 A1-L23-B18 1405 A1-L24-B18 1406 A1-L2-B18 1407 A1-L3-B18 1408 A1-L45-B18 1409 A1-L20-B19 1410 A1-L21-B19 1411 A1-L22-B19 1412 A1-L23-B19 1413 A1-L24-B19 1414 A1-L2-B19 1415 A1-L3-B19 1416 A1-L45-B19 1417 A4-L46-B10 1418 A4-L18-B10 1419 A4-L19-B10 1420 A4-L46-B15 1421 A4-L18-B15 1422 A4-L19-B15 1423 A4-L46-B16 1424 A4-L18-B16 1425 A4-L19-B16 1426 A4-L46-B6 1427 A4-L18-B6 1428 A4-L19-B6 1429 A1-L45-B10

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

In certain embodiments, provided is a compound having the structure:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.

Methods of Treatment

Provided herein are compounds which can be used to treat, prevent, and/or delay the onset and/or development of cancer. Accordingly, in certain embodiments, provided is a method for the treatment of cancer, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound or composition described herein. Certain embodiments provide a method of potentiation of cytotoxic cancer therapy in a subject in recognized need of such treatment comprising administering to the subject a therapeutically acceptable amount of a compound or composition described herein.

It is contemplated that a patient having any cancer may benefit from being treated with the compounds and compositions described herein. Accordingly, in certain embodiments, the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma. In certain embodiments, the cancer is bladder cancer, a blood cancer, such as leukemia (e.g., chronic leukemia, chronic lymphocytic leukemia (CLL, etc.) or lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, low grade lymphoma, high grade lymphoma), lung cancer (e.g., small cell lung cancer), breast cancer, fallopian tube cancer, glioblastoma multiforme, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer, testicular cancer, skin cancer (e.g., melanoma) or uterine cancer. In certain embodiments, the cancer is bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer.

In certain embodiments, the compounds and compositions as described herein are tailored to target cancers which overexpress a specific receptor, such as, but not limited to, androgen receptors, estrogen receptors, progesterone receptors, and/or glucocorticoid receptors by including an epitope which targets that specific nuclear receptor. The epitope can be derived from a steroid hormone or any non-steroidal drug which targets that particular receptor.

In certain embodiments, provided is a method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one androgen receptor-targeting epitope to an individual in need thereof. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, prostate, breast, triple negative breast cancer, bladder, or liver cancer. Also provided is a method of treating or preventing metastatic castration-resistant prostate cancer (mCRPC), comprising administering an effective amount of a compound or composition as described herein, or a pharmaceutically acceptable salt or solvate thereof, to an individual in need thereof.

In certain embodiments, provided is a method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one androgen receptor-targeting epitope to an individual in need thereof. In certain embodiments, the cancer is prostate, breast, triple negative breast cancer, bladder, or liver cancer. In certain embodiments, the androgen receptor-targeting epitope comprises an androgen receptor agonist, a selective androgen-receptor modulator (SARM), an androgen receptor antagonist, a selective estrogen receptor modulator (SERM), an estrogen receptor antagonist, a progestin, or an estrogen. In certain embodiments, the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, darolutamide, or an analog thereof.

In certain embodiments, the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, or an analog thereof. In certain embodiments, the nuclear payload comprises a PARP inhibitor.

In certain embodiments, provided is a method of treating or preventing an estrogen and/or progesterone receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one estrogen and/or progesterone receptor-targeting epitope to an individual in need thereof. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, breast, uterine, or ovarian cancer.

In certain embodiments, provided is a method of treating or preventing a glucocorticoid receptor overexpressing cancer, comprising administering an effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, comprising at least one nuclear payload and at least one glucocorticoid receptor-targeting epitope to an individual in need thereof. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, breast, uterine, or ovarian cancer. Specific cancers which are contemplated to be treated by such methods include, but are not limited to, prostate, possibly breast, uterine, ovarian.

Breast cancer includes ductal carcinoma in situ (DCIS) and invasive breast cancer. Breast cancers can occur in milk ducts, milk-producing lobules and connective tissues. Breast cancer includes estrogen receptor (ER) negative and hormone receptor (HR) negative, and also can be categorized as Group 3 (HER-2 positive) or Group 4 (basal-like).

Prostate cancer is a cancer which develops in the prostate, a gland in the male reproductive system. It occurs when cells of the prostate mutate and begin to multiply uncontrollably. These cells may metastasize (metastatic prostate cancer) from the prostate to virtually any other part of the body, particularly the bones and lymph nodes, but the kidney, bladder and even the brain, among other tissues. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, erectile dysfunction. Other symptoms can potentially develop during later stages of the disease. Rates of detection of prostate cancers vary widely across the world, with South and East Asia detecting less frequently than in Europe, and especially the United States. Prostate cancer develops most frequently in men over the age of fifty and is one of the most prevalent types of cancer in men. However, many men who develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. This is because cancer of the prostate is, in most cases, slow-growing, and because most of those affected are over the age of 60. Hence, they often die of causes unrelated to prostate cancer. Many factors, including genetics and diet, have been implicated in the development of prostate cancer. The presence of prostate cancer may be indicated by symptoms, physical examination, prostate specific antigen (PSA), or biopsy. There is concern about the accuracy of the PSA test and its usefulness in screening. Suspected prostate cancer is typically confirmed by taking a biopsy of the prostate and examining it under a microscope. Further tests, such as CT scans and bone scans, may be performed to determine whether prostate cancer has spread. Combination with primarily surgery and radiation therapy, or other treatments such as hormonal therapy, chemotherapy, proton therapy, cryosurgery, high intensity focused ultrasound (HIFU) are also contemplated.

Certain embodiments provide a method of inhibiting PARP in a subject in recognized need of such treatment comprising administering to the subject a therapeutically acceptable amount of a compound or composition described herein. In one embodiment, provided herein is a method of treating a disease ameliorated by the inhibition of PARP comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound or composition described herein.

Certain embodiments provide a method of treating leukemia, colon cancer, glioblastomas, lymphomas, melanomas, carcinomas of breast, or cervical carcinomas in a subject in recognized need of such treatment comprising administering to the subject a therapeutically acceptable amount of a compound or composition described herein.

In some embodiments, provided herein is a method of treatment of a cancer deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair pathway, which includes administering to a subject in need of treatment a therapeutically-effective amount of a compound or composition described herein. In certain embodiments, the cancer includes one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells. In some embodiments, the cancer cells have a BRCA1 or BRCA2 deficient phenotype. In some embodiments, the cancer cells are deficient in BRCA1 or BRCA2. In some embodiments, the methods provided herein involve treatment of an individual who is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway. In certain embodiment, the individual is heterozygous for a mutation in BRCA1 and/or BRCA2. In some embodiments, the method of treatment of a cancer includes treatment of breast, ovary, pancreas and/or prostate cancer. In some embodiments, the method of treatment of a cancer further includes administration of ionizing radiation or a chemotherapeutic agent.

The primary function of the DNA mismatch repair (MMR) system is to eliminate single-base mismatches and insertion-deletion loops that may arise during DNA replication. Insertion-deletion loops result from gains or losses of short repeat units within microsatellite sequences, also known as microsatellite instability (MSI). At least six different MMR proteins are required. For mismatch recognition, the MSH2 protein forms a heterodimer with either MSH6 or MSH3 depending on the type of lesion to be repaired (MSH6 is required for the correction of single-base mispairs, whereas both MSH3 and MSH6 may contribute to the correction of insertion-deletion loops). A heterodimer of MLH1 and PMS2 coordinates the interplay between the mismatch recognition complex and other proteins necessary for MMR. These additional proteins may include at least exonuclease 1 (EXO1), possibly helicase(s), proliferating cell nuclear antigen (PCNA), single-stranded DNA-binding protein (RPA), and DNA polymerases δ and ε. In addition to PMS2, MLH1 may heterodimerize with two additional proteins, MLH3 and PMS1. Recent observations indicate that PMS2 is required for the correction of single-base mismatches, and PMS2 and MLH3 both contribute to the correction of insertion-deletion loops. Additional homologs of the human MMR proteins are known that are required for functions other than MMR. These proteins include MSH4 and MSH5 that are necessary for meiotic (and possibly mitotic) recombination but are not presumed to participate in MMR.

Germline mutations of human MMR genes cause susceptibility to hereditary nonpolyposis colon cancer (HNPCC), one of the most common cancer syndromes in humans. An excess of colon cancer and a defined spectrum of extracolonic cancers, diagnosed at an early age and transmitted as an autosomal dominant trait, constitute the clinical definition of the syndrome. MSI, the hallmark of HNPCC, occurs in approximately 15% to 25% of sporadic tumors of the colorectum and other organs as well. According to international criteria, a high degree of MSI (MSI-H) is defined as instability at two or more of five loci or ≥30% to 40% of all microsatellite loci studied, whereas instability at fewer loci is referred to as MSI-low (MSI-L). MSI occurs in a substantial proportion (2% to 50% of tumors) among non-HNPCC cancers (e.g., cancers of the breast, prostate, and lung). On the basis of the proportion of unstable markers, categories MSS, MSI-L, and MSI-H can be distinguished in these cancers in analogy to HNPCC cancers. In one embodiment is a method for treating a cancer deficient in mismatch DNA repair pathway. In another embodiment is a method for treating a cancer demonstrating microsatellite instability due to reduced or impaired DNA repair pathways. In another embodiment is a method for treating a cancer demonstrating genomic instability due to reduced or impaired DNA repair pathways.

In certain embodiments, a compound or composition described herein, may be used in the preparation of a medicament for the treatment of cancer which is deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair activity, or in the treatment of a patient with a cancer which is deficient in HR dependent DNA DSB repair activity, which includes administering to said patient a therapeutically-effective amount of the compound or composition.

The HR dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix. The components of the HR dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE11A (NM_005590) and NBS11M_00248_5). Other proteins involved in the HR dependent DNA DSB repair pathway include regulatory factors such as EMSY (Wood, et al., Science, 291, 1284-1289 (2001); Khanna et al., Nat. Genet. 27(3): 247-254 (2001); and Hughes-Davies, et al., Cell, 115, pp 523-535).

In some embodiments, a cancer which is deficient in HR dependent DNA DSB repair includes one or more cancer cells which have a reduced or abrogated ability to repair DNA DSBs through that pathway, relative to normal cells, i.e. the activity of the HR dependent DNA DSB repair pathway are reduced or abolished in the one or more cancer cells.

In certain embodiments, the activity of one or more components of the HR dependent DNA DSB repair pathway is abolished in the one or more cancer cells of an individual having a cancer which is deficient in HR dependent DNA DSB repair. Components of the HR dependent DNA DSB repair pathway include the components listed above.

In some embodiments, the cancer cells have a BRCA1 and/or a BRCA2 deficient phenotype, i.e., BRCA1 and/or BRCA2 activity is reduced or abolished in the cancer cells. In certain embodiments, cancer cells with this phenotype are deficient in BRCA1 and/or BRCA2, i.e., expression and/or activity of BRCA1 and/or BRCA2 is reduced or abolished in the cancer cells, for example by means of mutation or polymorphism in the encoding nucleic acid, or by means of amplification, mutation or polymorphism in a gene encoding a regulatory factor, for example the EMSY gene which encodes a BRCA2 regulatory factor or by an epigenetic mechanism such as gene promoter methylation.

BRCA1 and BRCA2 are tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers. BRCA1 and/or BRCA2 mutations are associated with breast cancer. Amplification of the EMSY gene, which encodes a BRCA2 binding factor, is associated with breast and ovarian cancer (Jasin M., Oncogene, 21(58), 8981-93 (2002); Tutt, et al, Trends Mol. Med., 8(12), 571-6, (2002); and Radice, P. J., Exp Clin Cancer Res., 21(3 Suppl), 9-12 (2002)).

Carriers of mutations in BRCA1 and/or BRCA2 are also at elevated risk of cancer of the ovary, prostate and pancreas.

In some embodiments, the individual is heterozygous for one or more variations, such as mutations and polymorphisms, in BRCA1 and/or BRCA2 or a regulator thereof. The detection of variation in BRCA1 and BRCA2 is described, for example in EP 699 754, EP 705 903, Neuhausen, S. L. and Ostrander, E. A., Genet. Test, 1, 75-83 (1992); Janatova M., et al, Neoplasma, 50(4), 246-50 (2003). Determination of amplification of the BRCA2 binding factor EMSY is described in Hughes-Davies, et al., Cell, 115, 523-535.

In certain instances, mutations and polymorphisms associated with cancer are detected at the nucleic acid level by detecting the presence of a variant nucleic acid sequence or at the protein level by detecting the presence of a variant (i.e. a mutant or allelic variant) polypeptide.

In certain embodiments, it is contemplated that the compounds described herein are useful for patients who have relapsed or become refractory. The term “relapsed” refers to disease (or cancer) that reappears or grows again after a period of remission. The term “refractory” is used to describe when the cancer does not respond to treatment or when the response to treatment does not last very long. For example, the compounds herein may be useful for treating cancer in patients who have previously been treated with the cancer therapies described herein, e.g. enzalutamide.

Compositions

Compositions, including pharmaceutical compositions, of any of the compounds detailed herein are embraced by this disclosure. Thus, provided herein are pharmaceutical compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions provided herein may take a form suitable for oral, buccal, parenteral (e.g., intravenous, intramuscular, infusion or subcutaneous injection), nasal, topical or rectal administration, or a form suitable for administration by inhalation.

A compound as described herein may, in one aspect, be in a purified form. Compositions comprising a compound as described herein, or a salt thereof, are provided, such as compositions of substantially pure compounds. In some embodiments, a composition comprising a compound as described herein, or a salt thereof, is in substantially pure form. Unless otherwise stated, “substantially pure” refers to a composition which contains no more than 35% impurity, wherein the impurity denotes a compound other than the desired compound, or a salt thereof, which comprises the majority of the composition. In one variation, a composition of substantially pure compound, or a salt thereof, is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound, or a salt thereof, is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound, or a salt thereof, is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound, or a salt thereof, is provided wherein the composition contains or no more than 5% impurity. In another variation, a composition of substantially pure compound, or a salt thereof, is provided wherein the composition contains or no more than 3% impurity. In still another variation, a composition of substantially pure compound, or a salt thereof, is provided wherein the composition contains or no more than 1% impurity. In a further variation, a composition of substantially pure compound, or a salt thereof, is provided wherein the composition contains or no more than 0.5% impurity.

In certain embodiments, pharmaceutical compositions are formulated in any manner, including using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the active compounds into pharmaceutical compositions. In some embodiments, proper formulation is dependent upon the route of administration chosen. In various embodiments, any techniques, carriers, and excipients are used as suitable.

Provided herein are pharmaceutical compositions that include a compound described herein and a pharmaceutically acceptable diluent(s), excipient(s), and/or carrier(s). In addition, in some embodiments, the compounds described herein are administered as pharmaceutical compositions in which compounds described herein are mixed with other active ingredients, as in combination therapy.

A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. In certain embodiments, a pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, practicing the methods of treatment or use provided herein, includes administering or using a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein. In specific embodiments, the methods of treatment provided for herein include administering such a pharmaceutical composition to a mammal having a disease or condition to be treated. In one embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount varies widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In various embodiments, the compounds described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

In certain embodiments, the pharmaceutical compositions provided herein are formulated for intravenous injections. In certain aspects, the intravenous injection formulations provided herein are formulated as aqueous solutions, and, in some embodiments, in physiologically compatible buffers such as

Hank's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, the pharmaceutical compositions provided herein are formulated for transmucosal administration. In some aspects, transmucosal formulations include penetrants appropriate to the barrier to be permeated. In certain embodiments, the pharmaceutical compositions provided herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, and in one embodiment, with physiologically compatible buffers or excipients.

In certain embodiments, the pharmaceutical compositions provided herein are formulated for oral administration. In certain aspects, the oral formulations provided herein comprise compounds described herein that are formulated with pharmaceutically acceptable carriers or excipients. Such carriers enable the compounds described herein to be formulated as tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated.

In some embodiments, pharmaceutical compositions for oral use are obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are optionally added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

In certain embodiments, provided herein is a pharmaceutical composition formulated as dragee cores with suitable coatings. In certain embodiments, concentrated sugar solutions are used in forming the suitable coating, and optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. In some embodiments, dyestuffs and/or pigments are added to tablets, dragees and/or the coatings thereof for, e.g., identification or to characterize different combinations of active compound doses.

In certain embodiments, pharmaceutical compositions which are used include orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the push-fit capsules contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, in soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers are optionally added. In certain embodiments, the formulations for oral administration are in dosages suitable for such administration.

In certain embodiments, the pharmaceutical compositions provided herein are formulated for buccal or sublingual administration. In certain embodiments, buccal or sublingual compositions take the form of tablets, lozenges, or gels formulated in a conventional manner. In certain embodiments, parenteral injections involve bolus injection or continuous infusion. In some embodiments, formulations for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the pharmaceutical composition described herein is in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and optionally contains formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In some embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspensions also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In alternative embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

In some embodiments, the compounds described herein are administered topically. In specific embodiments, the compounds described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and/or preservatives.

In certain embodiments, the pharmaceutical compositions provided herein are formulated for transdermal administration of compounds described herein. In some embodiments, administration of such compositions employs transdermal delivery devices and transdermal delivery patches. In certain embodiments, the compositions are lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches include those constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In some embodiments, transdermal delivery of the compounds described herein is accomplished by use of iontophoretic patches and the like. In certain embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers are optionally used to increase absorption. Absorption enhancer and carrier include absorbable pharmaceutically acceptable solvents that assist in passage of the compound through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

In certain embodiments, the pharmaceutical compositions provided herein are formulated for administration by inhalation. In certain embodiments, in such pharmaceutical compositions formulated for inhalation, the compounds described herein are in a form as an aerosol, a mist or a powder. In some embodiments, pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain aspects of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator is formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.

In some embodiments, the compounds described herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas. In certain embodiments, rectal compositions optionally contain conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In certain suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

In various embodiments provided herein, the pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into pharmaceutically acceptable preparations. In certain embodiments, proper formulation is dependent upon the route of administration chosen. In various embodiments, any of the techniques, carriers, and excipients is used as suitable. In some embodiments, pharmaceutical compositions comprising a compound described herein are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

In certain embodiments, the pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and a compound described herein described herein as an active ingredient in free-acid or free-base form, or in a pharmaceutically acceptable salt form. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), as well as active metabolites of these compounds having the same type of activity. In some situations, compounds described herein exist as tautomers. All tautomers are included within the scope of the compounds presented herein. Additionally, included herein are the solvated and unsolvated forms of the compounds described herein. Solvated compounds include those that are solvated with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In some embodiments, the pharmaceutical compositions described herein include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, and/or buffers. In additional embodiments, the pharmaceutical compositions described herein also contain other therapeutically valuable substances.

Methods for the preparation of compositions containing the compounds described herein include formulating the compounds with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions and creams. In various embodiments, the compositions are in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

In some embodiments, a composition comprising a compound described herein takes the form of a liquid where the agents are present in solution, in suspension or both. In some embodiments, when the composition is administered as a solution or suspension a first portion of the agent is present in solution and a second portion of the agent is present in particulate form, in suspension in a liquid matrix. In some embodiments, a liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous.

Useful aqueous suspension optionally contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulosic polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Useful compositions optionally comprise an mucoadhesive polymer, selected for example from carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

Useful compositions optionally include solubilizing agents to aid in the solubility of a compound described herein. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Solubilizing agents include certain acceptable nonionic surfactants, for example polysorbate 80, and ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Useful compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

Useful compositions optionally include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

Certain useful compositions optionally include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal;

stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Some useful compositions optionally include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.

Certain useful compositions optionally one or more antioxidants to enhance chemical stability where required. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. In alternative embodiments, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

In various embodiments, any delivery system for hydrophobic pharmaceutical compounds is employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. In certain embodiments, certain organic solvents such as N-methylpyrrolidone are employed. In some embodiments, the compounds are delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials are utilized in the embodiments herein. In certain embodiments, sustained-release capsules release the compounds for a few weeks up to over 100 days. In some embodiments, depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization are employed.

In certain embodiments, the formulations or compositions described herein benefit from and/or optionally comprise antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

Dosing and Treatment Regimens

In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. In some embodiments, amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. In certain instances, it is considered appropriate for the caregiver to determine such therapeutically effective amounts by routine experimentation (including, but not limited to, a dose escalation clinical trial).

In certain prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. In some embodiments, the amount administered is defined to be a “prophylactically effective amount or dose.” In certain embodiments of this use, the precise amounts of compound administered depend on the patient's state of health, weight, and the like. In some embodiments, it is considered appropriate for the caregiver to determine such prophylactically effective amounts by routine experimentation (e.g., a dose escalation clinical trial). In certain embodiments, when used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

In certain instances, a patient's condition does not improve or does not significantly improve following administration of a compound or composition described herein and, upon the doctor's discretion the administration of the compounds is optionally administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

In certain cases wherein the patient's status does improve or does not substantially improve, upon the doctor's discretion the administration of the compounds are optionally given continuously; alternatively, the dose of drug being administered is optionally temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In certain embodiments, the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes a reduction from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

In certain embodiments, once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. In some embodiments, the dosage, e.g., of the maintenance dose, or the frequency of administration, or both, are reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, patients are optionally given intermittent treatment on a long-term basis upon any recurrence of symptoms.

In certain embodiments, the amount of a given agent that corresponds to an effective amount varies depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment. In some embodiments, the effective amount is, nevertheless, determined according to the particular circumstances surrounding the case, including, e.g., the specific agent that is administered, the route of administration, the condition being treated, and the subject or host being treated. In certain embodiments, however, doses employed for adult human treatment is in the range of about 0.02 to about 5000 mg per day, in a specific embodiment about 1 to about 1500 mg per day. In various embodiments, the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

In some embodiments, the pharmaceutical compositions described herein are in a unit dosage form suitable for single administration of precise dosages. In some instances, in unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. In certain embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. In some embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. In alternative embodiments, multiple-dose reclosable containers are used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection are, in some embodiments, presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

In certain embodiments, the daily dosages appropriate for the compounds described herein described herein are from about 0.01 to about 2.5 mg/kg per body weight. In some embodiments, an indicated daily dosage in the larger subject, including, but not limited to, humans, is in the range from about 0.5 mg to about 100 mg, conveniently administered in divided doses, including, but not limited to, up to four times a day or in extended release form. In certain embodiments, suitable unit dosage forms for oral administration comprise from about 1 to about 50 mg active ingredient. The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. In certain embodiments, the dosages are altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

In certain embodiments, toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD₅₀ and ED₅₀. In certain embodiments, compounds exhibiting high therapeutic indices are preferred. In some embodiments, the data obtained from cell culture assays and animal studies is used in formulating a range of dosage for use in human. In specific embodiments, the dosage of such compounds lies within a range of circulating concentrations that include the ED₅₀ with minimal toxicity. In certain embodiments, the dosage varies within this range depending upon the dosage form employed and the route of administration utilized.

In certain embodiments, the disclosed compounds exhibit an increased affinity for a nuclear target, increased potency or increased therapeutic index as compared to an unmodified nuclear payload from which the compound was derived. In certain embodiments, this higher affinity, potency or therapeutic index may provide benefits, such as allowing for the administration of lower doses and thus reduced potential for toxicity, improvement in therapeutic index and decreased overall cost of therapy. In certain embodiments, the daily dosages appropriate for administration of the compounds described herein is less than 100% of the recommended daily dose of the unmodified nuclear payload, or less than about 90%, or less than about 80% or less than about 70%, or less than about 60%, or less than about 50%, or less than about 40%, or from about 20% to about 90%, or from about 30% to about 90%, or from about 40% to about 90%, or from about 50% to about 90%, or from about 60% to about 90%, or from about 70% to about 90%, or from about 20% to about 80%, or from about 30% to about 80%, or from about 40% to about 80%, or from about 50% to about 80%, or from about 60% to about 80%, or from about 70% to about 80%, or from about 20% to about 70%, or from about 30% to about 70%, or from about 40% to about 70%, or from about 50% to about 70%, or from about 60% to about 70%, of the recommended daily dose of the unmodified nuclear payload.

In certain embodiments, the compounds described herein are used in the preparation or manufacture of medicaments for the treatment of diseases or conditions that are mediated by the enzyme poly(ADP-ribose)polymerase (PARP) or in which inhibition of the enzyme poly(ADP-ribose)polymerase (PARP) ameliorates the disease or condition. In some embodiments, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

Combination Therapy

Compounds described herein (e.g., a compound of Table 1, a compound of Formula I or II, or any other formula disclosed herein) can also be used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. In one embodiment, the disclosure provides a use of a compound as described herein used in combination with another agent or therapy method, such as another cancer treatment. For example, when treating cancer, the compositions can be combined with other anti-cancer compounds (such as paclitaxel or rapamycin).

It is also possible to combine a compound of the disclosure with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

The combination therapy may provide “synergy” and “synergistic”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. A synergistic anti-cancer effect denotes an anti-cancer effect that is greater than the predicted purely additive effects of the individual compounds of the combination.

Administration of the compounds and compositions of the present disclosure to a patient will follow general protocols for the administration of chemotherapeutics, taking into account the toxicity, if any. It is expected that the treatment cycles would be repeated as necessary. It also is contemplated that various standard therapies or adjunct cancer therapies, as well as surgical intervention, may be applied in combination with the described active agent(s). These therapies include but are not limited to chemotherapy, radiotherapy, immunotherapy, gene therapy and surgery.

In some embodiments, provided herein is a method for the treatment of cancer, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound or composition described herein in combination with ionizing radiation or one or more chemotherapeutic agents. In some embodiments, the compound described herein is administered simultaneously with ionizing radiation or one or more chemotherapeutic agents. In other embodiments, the compound described herein is administered sequentially with ionizing radiation or one or more chemotherapeutic agents.

In certain embodiments, provided herein is a method for the treatment of cancer, which includes administering to a subject in need of treatment a therapeutically-effective amount of a compound or composition described herein in combination with ionizing radiation and one or more chemotherapeutic agents. In some embodiments, the compound described herein is administered simultaneously with ionizing radiation and one or more chemotherapeutic agents. In other embodiments, the compound described herein is administered sequentially with ionizing radiation and one or more chemotherapeutic agents.

In certain embodiments, provided herein is a method for the treatment of cancer, which includes administering to a subject in need of treatment a therapeutically-effective amount of a compound or composition described herein in combination with ionizing radiation. In certain embodiments, the radiation is administered at a dose of less than about 2.5 Gy per day, or about 2.0 Gy per day, or about 1.8 Gy per day, or about 1.6 Gy per day, or about 1.4 Gy per day, or about 1.2 Gy per day. In certain embodiments, a dose of less than about 2.5 Gy, or about 2.0 Gy, or about 1.8 Gy, or about 1.6 Gy, or about 1.4 Gy, or about 1.2 Gy is administered about 5 times per week. In certain embodiments, the radiation is administered at a dose of less than about 2.5 Gy per day, or about 2.0 Gy per day, or about 1.8 Gy per day, or about 1.6 Gy per day, or about 1.4 Gy per day, or about 1.2 Gy per day. In certain embodiments, a dose of less than about 2.5 Gy, or about 2.0 Gy, or about 1.8 Gy, or about 1.6 Gy, or about 1.4 Gy, or about 1.2 Gy is administered about 6 times per week. It is contemplated that by administering radiation in combination with a compound or composition described herein, prostate specific chemical prostatectomy can be achieved while avoiding detrimental side effects, such as the impotence and incontinence of surgical prostatectomy due to disruption of vessels and nerves.

Cancer therapies can also include a variety of combination therapies with both chemical and radiation based treatments. Combination chemotherapies include the use of chemotherapeutic agents such as, cisplatin, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, taxotere, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA® (gefitinib), TARCEVAR® (erlotinib hydrochloride), antibodies to EGFR, GLEEVEC® (imatinib), intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, vinblastine, vincristine, vindesine, bleomycin, doxorubicin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, Mitomycin-C, L-Asparaginase, teniposide, 17α-Ethinylestradiol, Diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux® (cetuximab), Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, Campath, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, paclitaxel, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine and methotrexate, or any analog or derivative variant of the foregoing.

Other factors that cause DNA damage, such as radiotherapy, have been used extensively include what are commonly known as gamma-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors are also contemplated such as microwaves and UV-irradiation. It is most likely that all of these factors affect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (e.g., 3 to 4 weeks), to single doses of 2000 to 6000 roentgens. Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells. The terms “contacted” and “exposed,” when applied to a cell, are used herein to describe the process by which a therapeutic construct and a chemotherapeutic or radiotherapeutic agent are delivered to a target cell or are placed in direct juxtaposition with the target cell. To achieve cell killing or stasis, both agents are delivered to a cell in a combined amount effective to kill the cell or prevent it from dividing.

Immunotherapeutics, generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells. The immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell. The antibody alone may serve as an effector of therapy or it may recruit other cells to actually affect cell killing. The antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionucleotide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent. Alternatively, the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target. Various effector cells include cytotoxic T cells and NK cells.

Immunotherapy, thus, could be used as part of a combined therapy, in conjunction with gene therapy. The general approach for combined therapy is discussed below. Generally, the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells. Many tumor markers exist and any of these may be suitable for targeting in the context of the present disclosure. Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and p155.

In yet another embodiment, the secondary treatment is a secondary gene therapy in which a therapeutic polynucleotide is administered before, after, or at the same time a first chemotherapeutic agent. Delivery of the chemotherapeutic agent in conjunction with a vector encoding a gene product will have a combined anti-hyperproliferative effect on target tissues.

Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative and palliative surgery. Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the treatment of the present disclosure, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies. Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed. Tumor resection refers to physical removal of at least part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). It is further contemplated that the present disclosure may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue.

Administration of the compound or composition as described herein may precede or follow the other anti-cancer agent or treatment by intervals ranging from minutes to weeks. In embodiments where the other anti-cancer agent and expression construct are applied separately, one would generally ensure that a significant period of time did not elapse between the time of each delivery, such that the agent and expression construct would still be able to exert an advantageously combined effect on a cell. For example, in such instances, it is contemplated that one may contact a cell, tissue or organism with two, three, four or more modalities substantially simultaneously (i.e., within less than about a minute) with the active agent(s). In other aspects, one or more agents may be administered within about 1 minute, about 5 minutes, about 10 minutes, about 20 minutes about 30 minutes, about 45 minutes, about 60 minutes, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 9 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, about 28 hours, about 31 hours, about 35 hours, about 38 hours, about 42 hours, about 45 hours, to about 48 hours or more prior to and/or after administering the active agent(s). In certain other embodiments, an agent may be administered within from about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 8 days, about 9 days, about 12 days, about 15 days, about 16 days, about 18 days, about 20 days, to about 21 days prior to and/or after administering the active agent(s). In some situations, it may be desirable to extend the time period for treatment significantly, however, where several weeks (e.g., about 1, about 2, about 3, about 4, about 6, or about 8 weeks or more) lapse between the respective administrations.

Kits

Kits for use to achieve anti-cancer effects comprising a compound or composition described herein are provided. In certain embodiments, the kit comprises a unit dose of a compound or composition described herein and instructions for administering the same. In certain aspects, the kit further comprises a second drug suitable for anti-cancer therapy, or instructions for co-administering an additional anti-cancer therapy (such as radiation or gene therapy). In another aspect, kits for use to achieve anti-cancer effects comprise a low dose (e.g., less than about 500 mg/day, or less than about 400 mg/day, or less than about 300 mg/day, or less than about 200 mg/day) of a compound or composition described herein and a second drug suitable for anti-cancer therapy. In yet another variation, kits for use to achieve anti-cancer effects comprise a high dose (e.g., greater than about 500 mg/day) of a compound or composition as described herein and a second drug suitable for anti-cancer therapy.

Methods of Manufacturing a Medicament

In a further aspect of the disclosure, use of the compounds and compositions described herein in the manufacture of a medicament is provided. In particular, the manufacture of a medicament for use in the treatment of cancer, or diseases or conditions which can be mediated, at least in part, by blocking DNA repair and/or transcription activation, such as by inhibition of PARP, are provided. Further, pharmaceutical compositions of a compound described herein are also intended for use in the manufacture of a medicament for use in treatment of diseases or conditions which can be mediated, at least in part, by inhibition of PARP.

EXAMPLES

The disclosure is further illustrated by the following examples. The examples below are non-limiting are merely representative of various aspects of the disclosure. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated.

Compounds as disclosed herein, or any formula or sub-formula described herein, can be synthesized using standard synthetic techniques known to those of skill in the art. Compounds of the present disclosure can be synthesized using the general synthetic procedures set forth in General Methods 1-5 Synthetic Examples.

Where it is desired to obtain a particular enantiomer of a compound, this may be accomplished from a corresponding mixture of enantiomers using any suitable conventional procedure for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives may be produced by reaction of a mixture of enantiomers, e.g., a racemate, and an appropriate chiral compound. The diastereomers may then be separated by any convenient means, for example by crystallization and the desired enantiomer recovered. In another resolution process, a racemate may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described.

Chromatography, recrystallization and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction.

¹H NMR spectra and ¹³C NMR spectra were recorded on Varian 400 MHz or Bruker Avance III 500 MHz spectrometers. Spectra are referenced to residual chloroform (δ 7.26, ¹H), DMSO (δ 2.54, ¹H) or methanol (δ 3.34, ¹H) unless otherwise noted. Chemical shifts are reported in ppm (δ); multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sext (sextet), m (multiplet) and br (broad). Coupling constants, J, are reported in Hertz. Silica gel chromatography was performed using a Teledyne Isco CombiFlash® Rf+ instrument using Hi-Purit Silica Flash Cartridges (National Chromatography Inco) or RediSep Rf Gold C18 Cartridges (Teledyne Isco). Analytical HPLC was performed on a Waters ACQUITY UPLC with a photodiode array detector using and a Waters ACQUITY BEH Shield RPC18 (2.1×50 mm, 1.7 μm) column. Analytical LCMS was performed on a Waters ACQUITY UPLC with a Waters 3100 mass detector. Chiral HPLC was performed on a Waters Alliance e2695 with a photodiode array detector using Daicel Chiralpak® AD-H, Chiralpak® IA, Chiralpak® IB, Chiralpak® IC, Chiralcel® OD-H or Chiralcel® OJ-H columns. Optical rotations were obtained on a Jasco P-2000 digital polarimeter and are reported as [α]_(D) ^(T) temperature (T), concentration (c=g/100 mL) and solvent. Commercially available reagents and solvents were used as received unless otherwise indicated.

General Methods General Method I

Olaparib-containing analogs can be prepared following the method described by Menear et al. (Menear, K. A. et al. J. Med. Chem. 2008, 51, 6581-6591).

General Method 2

Rucaparib-containing analogs can be prepared following the method described by Gillmore et. al. (Gillmore, A. T. et al. Org. Process Res. Dev. 2012, 16, 1897-1904).

General Method 3

Talazoparib-containing analogues can be prepared following the method described by Wang et al. (Wang, B. et al. J. Med. Chem. 2016, 59, 335-357).

General Method 4

DHT-containing intermediates can be prepared by treating commercially available DHT (XX) with the desired tethering group to afford intermediates such as XXI. When R═CO₂Me, the ester group can be mildly saponified to provide the carboxylate intermediates A. When R═OAc, mild saponification releases the primary alcohol which can then be treated with methanesulfonyl chloride to afford intermediates B.

General Method 5

Enzalutamide-containing intermediates can be prepared starting with carboxylic acid XXII (Jadhavar, et al. Bioorg. Med. Chem. Lett. 2016, 26, 5222-5228) and coupling with the desired tethering group to afford intermediates such as XXIII. When R═CO₂Me, the ester group can be mildly saponified to provide the carboxylate intermediates C. When R═OAc, mild saponification releases the primary alcohol which can then be treated with methanesulfonyl chloride to afford intermediates D.

General Method 6

CC-115 containing analogs can be prepared following the method described by Mortensen et al. (Mortensen, D. S. et al. J. Med. Chem. 2015, 58, 5599-5608).

The compounds of Table 1 can be prepared according to the general experimental details exemplified above using the appropriate starting materials and reagents. Exemplary compounds described herein can be or were prepared according to the following Synthetic Methods.

Synthetic Methods Synthetic Method 1

Synthetic Method 2

Synthetic Method 3

Synthetic Method 4

Synthetic Method 5

Synthetic Method 6 Example S-1. Preparation of 6-((5R,8R,9S,10S,13S,14S,17R)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)-N-(4-48S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)phenyl)hexanamide (1128)

Step-1a: Preparation of 2-(6-chlorohexyloxy)tetrahydro-2H-pyran

To a stirred solution of 6-chlorohexan-1-ol (10 g, 73.5 mmol) in diethyl ether (100 mL) was added PTSA (1.4 g, 7.35 mmol, 0.1 eq) followed by addition of 3,4-dihydro-2H-pyran (7.41 g, 88.0 mmol, 1.2 eq) at RT and the mixture was stirred at RT for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was diluted with water (200 mL) and extracted with EtOAc (350 mL). The organic layer was washed with saturated NaHCO₃ solution (100 mL), water (200 mL), brine (100 mL) dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound which was taken to next step without further purification.

Step-1: Preparation of 2-(6-((5R,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexyloxy)tetrahydro-2H-pyran

To a stirred solution of (5R,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-ol (1.0 g, 2.40 mmol) in xylene (10 mL) was added NaNH₂ (50% suspension in toluene, 3 mL) and the mixture was heated at 150° C. for 1 h. The reaction mixture was gradually cooled to RT, 2-(6-chlorohexyloxy)tetrahydro-2H-pyran (4.2 g, 24.0 mmol)) was added to it and the resultant mixture was again heated to 150° C. for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was cooled to RT, quenched slowly with ice cold water (250 mL) and extracted with EtOAc (300 mL). The organic layer was washed with water (100 mL×2), brine (100 mL) dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash chromatography to afford the title compound.

Step-2: Preparation of 6-((5R,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexan-1-ol

To a stirred solution of 2-(6-((5R,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexyloxy)tetrahydro-2H-pyran (1.0 g, 2.17 mmol, 1 eq) in THF (28 mL) —H₂O (7 mL) was added 6N—HCl (20 mL) at RT and the mixture was stirred at RT for 16 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (150 mL) and basified using with saturated NaHCO₃ solution (pH˜8). The aqueous layer was then extracted with EtOAc (200 mL×3). The organic layer was washed with saturated NaHCO₃ solution (100 mL), water (100 mL), brine (100 mL) dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound which was used in the next step without further purification.

Step-3: Preparation of 6-((5R,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexanoic acid

To a stirred solution of 6-((5R,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexan-1-ol (0.40 g, 1.09 mmol, 1 eq) in acetone (25 mL) was added Jones reagent (1.2 mL) at 0° C. dropwise over a period of 20 min. The resultant mixture was stirred at 0° C. for 5 min. The reaction was monitored by TLC. After completion, H₂O (20 mL) was added and the resulting precipitate was filtered over Buchner funnel. The product obtained was washed with water (5 mL×2) and n-pentane (5 mL×2), dried under vacuum to afford the title compound which was taken to next step without further purification.

Step-4:Preparation of 6-((5R,8R,9S,10S,13S,14S,17R)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)-N-(4-((8S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)phenyl)hexanamide

To a stirred solution of 6-((5R,8R,9S,10S,13S,14S,17R)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexanoic acid (0.1 g, 0.25 mmol) in DMF (7 mL) was added HATU (0.142 g, 0.375 mmol, 1.5 eq) at 0° C. and the mixture was stirred at same temperature for 30 min. DIPEA (0.22 mL, 1.25 mmol, 5 eq) and (8S,9R)-8-(4-aminophenyl)-5-fluoro-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (0.066 g, 0.175 mmol, 0.7 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted using EtOAc (100 mL×2). The combined organic layers were washed with saturated NaHCO₃ solution (100 mL), saturated NH₄Cl solution (100 mL), water (100 mL), brine (50 mL) dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford a crude product which was purified by reversed phase HPLC to afford the title compound. LC-MS 750 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s, 1H), 9.86 (s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.05 (dd, J=2.2, 8.8 Hz, 1H), 6.92 (dd, J=2.4, 11.2 Hz, 1H), 5.00-4.80 (m, 2H), 3.64 (s, 3H), 3.31-3.19 (m, 4H), 2.26 (t, J=7.2 Hz, 2H), 1.77 (d, J=11.0 Hz, 2H), 1.66-1.04 (m, 16H), 1.04-0.77 (m, 5H), 0.75 (s, 4H), 0.68-0.55 (m, 3H).

Synthetic Method 7 Example S-2. Preparation of 4-(4-fluoro-3-(4-(6-((8S,11S,13S,14S)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)hexanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (1370)

Step-1: Preparation of (8S,13S,14S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro spiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol

To a solution of (8S,13S,14S)-13-methyl-1,2,6,7,8,12,13,14,15,16-decahydrospiro[cyclopenta [a]phenanthrene-3,2′-[1,3]dioxolan]-17(4H)-one (5 g, 15.9 mmol) (purchased from TCI Chemicals) in THF (50 mL) and MeOH (5 mL) was added sodium borohydride (2.94 g, 7.9 mmol) in portions at 0° C. The mixture was stirred at 0° C. for 30 min and then RT for 1 h. The reaction was quenched with 20 mL of sat. NaHCO₃ solution and concentrated to remove MeOH. The residue was dissolved in EtOAc (300 mL). The organic phase was washed with sat NaHCO₃ solution (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated to afford the title compound. LCMS: 317 [M+H]⁺

Step-2: Preparation of (5R,10R,13S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro spiro[5,10-epoxycyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol

To a solution of (8S,13S,14S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro spiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol (5 g, 15.8 mmol) in DCM (40 mL) at 0° C. was added Na₂HPO₄ (1.12 g, 7.9 mmol), followed by addition of 1,1,1,3,3,3-hexafluoropropan-2-one trihydrate (2.1 g, 9.5 mmol) and H₂O₂ (35% aq, 3.8 mL, 47.4 mmol). The mixture was stirred at 0° C. for 10 min and then at RT for 3 h. Sodium thiosulfate solution (10% aq, 30 mL) was slowly added at 0° C., and the mixture was stirred at RT for 30 min and extracted with DCM (200 mL×2). The organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated to afford the title compound. LCMS: 333 [M+H]⁺

Step-3: Preparation of (8S,11S,13S,14S,17S)-11-(6-(tert-butyldimethylsilyloxy)hexyl)-17-hydroxy-13-methyl-6,7,8,11,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

A dried flask was charged with magnesium turnings (0.36 g, 15 mmol) and a crystal of iodine. The flask was flushed with nitrogen and heated briefly with a heat gun and then put into a 60° C. of bath. A solution (6-bromohexyloxy)(tert-butyl)dimethylsilane (2.2 g, 15 mmol) in THF (20 mL) was added. After the iodine color disappeared, the remaining solution was added dropwise for 20 min and the mixture was continued to stir at 60° C. for 2 h. The generated (6-(tert-butyldimethylsilyloxy)hexyl)magnesium bromide Grignard reagent prepared above was cooled down and added to a solution of (5R,10R,13S,17S)-13-methyl-1,2,4,6,7,8,12,13,14,15,16,17-dodecahydro spiro[5,10-epoxycyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol (0.5 g, 1.50 mmol) and copper (I) iodide (0.23 g, 1.2 mmol) in THF (30 mL) at 0° C. The resulting mixture was allowed to warm up to RT and stir for 1 h. The reaction was quenched with sat NH₄Cl, extracted with (2×100 mL) and washed with brine (20 mL). The combined organic layer was dried under Na₂SO₄ and concentrated under reduced pressure to afford crude product which was purified by CombiFlash chromatography to afford the title compound. LCMS: 487 [M+H]⁺

Step-4: Preparation of (8S,11S,13S,14S,17S)-17-hydroxy-11-(6-hydroxyhexyl)-13-methyl-6,7,8,11,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To (8S,11S,13S,14S,17S)-11-(6-(tert-butyldimethylsilyloxy)hexyl)-17-hydroxy-13-methyl-6,7,8,11,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (0.32 g, 0.64 mmol) was added TBAF (3 mL) slowly & the mixture was stirred at 0° C. for 1 h. After completion of reaction, the mixture was quenched with ice-cold water (30 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the title compound. LCMS: 373 [M+H]⁺

Step-5: Preparation of 6-((8S,11S,13S,14S)-13-methyl-3,17-dioxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)hexanoic acid

A solution of (8S,11S,13S,14S,17S)-17-hydroxy-11-(6-hydroxyhexyl)-13-methyl-6,7,8,11,12,13, 14, 15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (0.24 g, 3.9 mmol, 1 eq) in acetone (50 mL) was added Jones reagent (2 mL) at 0° C. dropwise over a period of 20 min. The resultant mixture was stirred at 0° C. for 5 min. The reaction was monitored by TLC. After completion, water (200 mL) was added and the resulting precipitate was filtered through a Büchner funnel. The solid obtained was washed with water (50 mL×2) and n-pentane (25 mL×2) and dried under vacuum to afford the title compound. LCMS: 385 [M+H]⁺

Step-6: Preparation of (8S,11S,13S,14S)-11-(6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-6-oxohexyl)-13-methyl-7,8,11,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione

To a stirred solution of 6-((8S,11S,13S,14S)-13-methyl-3,17-dioxo-2,3,6,7,8,11,12,13, 14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)hexanoic acid (0.53 g, 0.92 mmol, 1.0 eq) in DMF (10 mL) was added HATU (0.52 g, 1.38 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.64 mL, 3.68 mmol, 4.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.26 g, 0.73 mmol, 0.8 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered through a Buchner funnel to obtain a crude which was purified by reversed phase HPLC to afford the title compound. LCMS: 733 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.89 (t, J=7.6 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.35 (d, J=5.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 1H), 5.61 (s, 1H), 4.33 (s, 2H), 3.59 (d, J=22.1 Hz, 2H), 3.37 (s, 1H), 3.23-3.10 (m, 2H), 3.02 (d, J=14.5 Hz, 1H), 2.83 (d, J=14.3 Hz, 1H), 2.42-1.11 (m, 28H), 0.99 (d, J=4.0 Hz, 3H).

Synthetic Method 8 Example S-3. Preparation of 4-(4-fluoro-3-(4-(6-((8S,11S,13S,14S)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)hexanoyl) piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (138)

Step-1: Preparation of 4-(4-fluoro-3-(4-(6-((8S,11S,13S,14S)-17-hydroxy-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)hexanoyl) piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one

To a stirred solution of (8S,11S,13S,14S)-11-(6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-6-oxohexyl)-13-methyl-7,8,11,12,13,14,15,16-octahydro-1H-cyclopenta[a]phenanthrene-3,17(2H,6H)-dione (0.04 g, 0.054 mmol) in MeOH:THF (1:1) (2 mL) was added NaBH₄ (0.001 g, 0.027 mmol, 0.5 eq) at RT and the reaction was stirred at same temperature for 20 min. The reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure and the residue obtained was diluted with EtOAc (40 mL). The organic layer was washed with H₂O (2×20 mL), brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash chromatography to afford the title compound. LCMS: 735 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 8.26 (dd, J=1.5, 8.1 Hz, 1H), 8.01-7.92 (m, 1H), 7.89 (br. s., 1H), 7.87-7.80 (m, 1H), 7.43 (d, J=4.4 Hz, 1H), 7.39-7.32 (m, 1H), 7.24 (t, J=9.4 Hz, 1H), 5.57 (br. s., 1H), 4.56 (m, 1H), 4.33 (s, 2H), 3.62 (br. s., 1H), 3.56 (d, J=2.6 Hz, 1H), 3.51 (br. s., 2H), 3.42 (d, J=4.8 Hz, 2H), 3.15 (d, J=19.7 Hz, 3H), 2.97 (br. s., 2H), 2.88-2.79 (m, 2H), 2.38-2.22 (m, 7H), 1.83 (br. s., 2H), 1.48 (br. s., 4H), 1.41-1.16 (m, 12H), 0.95-0.75 (m, 4H).

Synthetic Method 9 Example S-4. Preparation of 4-(4-fluoro-3-(4-(6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-ynyl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (135)

Step-1: Preparation of (8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-(4-(methylamino)phenyl)-17-(prop-1-ynyl)-6,7,8,11,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of (8S,11R,13S,14S,17S)-11-(4-(dimethylamino)phenyl)-17-hydroxy-13-methyl-17-(prop-1-ynyl)-6,7,8,11,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (3.6 g, 8.39 mmol, 1.0 eq) in MeOH:THF (1:1) (72 mL) was added CaO (5.3 g, 20.90 mmol, 9 eq) at 0° C., followed by dropwise addition of iodine (5.3 g, 20.9 mmol, 2.5 eq) dissolved in THF (10 mL). The mixture was stirred at 0° C. for 1 h. The progress of reaction was monitored by LC-MS. After 1 h, the mixture was quenched with saturated solution of Na₂S₂O₃ (100 mL) at 0° C. slowly. The mixture was filtered and the filtrate was extracted with DCM (300 mL×3). The combined organic layers were washed with water (400 mL), brine (200 mL), dried over Na₂SO₄ and concentrated under reduced pressure to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 416 [M+H]⁺

Step-2: Preparation of 6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-ynyl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexanoic acid

To a stirred solution of 6-bromohexanoic acid (3.87 g, 19.85 mmol, 5.0 eq) in EtOH:H₂O (1:1) (50 mL) was added NaHCO₃ (˜pH=8) followed by addition of (8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-11-(4-(methylamino)phenyl)-17-(prop-1-ynyl)-6,7,8,11,12,13,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (1.65 g, 3.97 mmol, 1.0 eq) and the resultant mixture was heated at 80° C. for 16 h. The progress of reaction was monitored by LC-MS. After 16 h, 1.25 M ethanolic HCl was slowly added to the reaction mixture (pH˜6) and the mixture was concentrated. To this was added water (200 mL) and extracted with DCM (200 mL×2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na₂SO₄, concentrated to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 530 [M+H]⁺

Step-3: Preparation of 4-(4-fluoro-3-(4-(6-((4-(8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-ynyl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one

To a stirred solution of 6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-ynyl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexanoic acid (0.25 g, 0.47 mmol, 1.0 eq) in DMF (10 mL) was added HATU (0.26 g, 0.70 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.33 mL, 1.88 mmol, 4.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.14 g, 0.37 mmol, 0.8 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered over Büchner funnel to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 878 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 8.29-8.22 (m, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.89 (td, J=7.6, 1.6 Hz, 1H), 7.83 (t, J=6.2 Hz, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.36 (d, J=4.9 Hz, 1H), 7.24 (t, J=9.0 Hz, 1H), 6.99-6.91 (m, 2H), 6.59 (d, J=8.2 Hz, 2H), 5.64 (s, 1H), 5.11 (s, 1H), 4.33 (s, 3H), 3.61 (s, 1H), 3.56 (s, 1H), 3.50 (s, 2H), 3.36 (s, 1H), 3.24 (d, J=7.8 Hz, 2H), 3.14 (dd, J=11.7, 6.8 Hz, 2H), 2.82 (d, J=2.7 Hz, 3H), 2.79-2.70 (m, 1H), 2.42-1.13 (m, 23H), 1.13-0.80 (m, 4H), 0.40 (d, J=3.9 Hz, 3H)

Synthetic Method 10 Example S-5. Preparation of N-(2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethyl)-6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-ynyl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexanamide (1429)

Step-1: Preparation of tert-butyl 2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethylcarbamate

To a stirred solution of 2-[2-(Boc-amino)ethoxy]ethoxyacetic acid (0.71 g, 2.73 mmol, 1.0 eq) in DMF (15 mL) was added HATU (1.6 g, 4.23 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (1.94 mL, 10.92 mmol, 4.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (1 g, 2.73 mmol, 1 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with water (40 mL), brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 612 [M+H]⁺

Step-2: Preparation of 4-(3-(4-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

To a solution of tert-butyl 2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethylcarbamate (1 g, 1.63 mmol, 1.0 eq) was dissolved in dioxane (3 mL), followed by dropwise addition of 4.0 M HCl in dioxane (10 mL) and allowed to stir at RT for 2 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to obtain crude which was purified by column chromatography to afford the title compound. LCMS: 512 [M+H]⁺

Step-3: Preparation of N-(2-(2-(2-(4-(2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethyl)-6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-ynyl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-H1-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexanamide

To a stirred solution of 6-((4-((8S,11R,13S,14S,17S)-17-hydroxy-13-methyl-3-oxo-17-(prop-1-ynyl)-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl)(methyl)amino)hexanoic acid (250 mg, 0.47 mmol, 1.0 eq) in DMF (10 mL) was added HATU (267 mg, 0.70 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.33 mL, 1.88 mmol, 4.0 eq) and 4-(3-(4-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (189 mg, 0.37 mmol, 0.8 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered through a Buchner funnel to obtain a crude which was purified by reversed phase HPLC to afford the title compound. LCMS: 1024 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 9.30 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.00-7.78 (m, 3H), 7.43 (dd, J=9.1, 5.2 Hz, 1H), 7.37 (d, J=6.0 Hz, 1H), 7.23 (t, J=9.1 Hz, 1H), 6.95 (d, J=8.0 Hz, 2H), 6.57 (d, J=8.0 Hz, 2H), 5.64 (s, 1H), 5.11 (s, 1H), 4.32 (s, 3H), 4.18 (s, 1H), 4.12 (s, 1H), 3.55 (m, 8H), 3.38 (d, J=7.4 Hz, 2H), 3.24-3.03 (m, 15H), 2.83-2.69 (m, 4H), 2.59 (s, 6H), 2.26-1.39 (m, 6H), 1.34 (d, J=5.9 Hz, 1H), 1.33-1.21 (m, 8H), 1.18 (t, J=7.3 Hz, 1H).

Synthetic Method 11 Example S-6. Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-6-oxohexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (1378)

Step-1: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate

To a stirred solution of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-(dimethylamino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (5.0 g, 10.51 mmol, 1.0 eq) in MeOH:H₂O (2:3) (60 mL) was added CaO (5.0 g, 89.36 mmol, 8.5 eq) −30° C., followed by dropwise addition of iodine (6.67 g, 26.28 mmol, 2.5 eq) dissolved in THF (5.0 mL). The mixture was stirred at −30° C. for 2.5 h. The progress of reaction was monitored by LC-MS. After 2.5 h, the mixture was quenched with saturated solution of Na₂S₂O₃ (50 mL) at 0° C. slowly. The mixture was filtered and the filtrate was extracted with DCM (300 mL×3). The combined organic layers were washed with water (400 mL), brine (200 mL), dried over Na₂SO and concentrated under reduced pressure to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 462 [M+H]⁺

Step-2: Preparation of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl) (methyl) amino) hexanoic acid

To a stirred solution of 6-bromohexanoic acid (10.56 g, 54.16 mmol, 5.0 eq) in EtOH:H₂O (1:1) (40 mL) was added NaHCO₃ (pH ˜8) followed by addition of (8S,11R,13S,14S,17R)-17-acetyl-13-methyl-11-(4-(methylamino) phenyl)-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (5.0 g, 10.83 mmol, 1.0 eq) and the resultant mixture was heated at 80° C. for 16 h. The progress of reaction was monitored by LC-MS. After 16 h, 1.25 M ethanolic HCl was slowly added to the reaction mixture (pH ˜6) and the mixture was concentrated. To this was added water (200 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na₂SO₄, concentrated to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 576 [M+H]⁺

Step-3: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-6-oxohexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate

To a stirred solution of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl) (methyl) amino) hexanoic acid (0.53 g, 0.92 mmol, 1.0 eq) in DMF (10 mL) was added HATU (0.53 g, 1.38 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.64 mL, 3.68 mmol, 4.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.26 g, 0.73 mmol, 0.8 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered through a Buchner funnel to obtain a crude which was purified by Reversed Phase HPLC to afford the title compound. LCMS: 924 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.61 (br. s., 1H), 8.26 (d, J=7.5 Hz, 1H), 7.95 (m, 1H), 7.89 (m, 1H), 7.83 (m, 1H), 7.44 (m, 1H), 7.36 (m, 1H), 7.24 (m, 1H), 6.96 (m, 2H), 6.57 (d, J=7.9 Hz, 2H), 5.67 (br. s., 1H), 4.38 (m, 1H), 4.33 (m, 2H), 3.61 (m, 1H), 3.55 (m, 4H), 3.49 (m, 2H), 3.22 (m, 2H), 3.14 (m, 2H), 2.81 (m, 2H), 2.74 (m, 3H), 2.32 (m, 2H), 2.25 (m, 2H), 2.16 (m, 1H), 2.10 (m, 3H), 1.99 (m, 3H), 1.69 (m, 2H), 1.48 (m, 4H), 1.27 (m, 4H), 0.22 (br. s., 3H).

Synthetic Method 12 Example S-7. Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethylamino)-6-oxohexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (1384)

Step-1: Preparation of tert-butyl 2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethylcarbamate

To a stirred solution of 2-[2-(Boc-amino)ethoxy]ethoxyacetic acid (0.71 g, 2.73 mmol, 1.0 eq) in DMF (15 mL) was added HATU (1.6 g, 4.23 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (1.94 mL, 10.92 mmol, 4.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (1 g, 2.73 mmol, 1 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with water (40 mL), brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 612 [M+H]⁺

Step-2: Preparation of 4-(3-(4-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

tert-Butyl 2-(2-(2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethylcarbamate (1 g, 1.63 mmol, 1.0 eq) was dissolved in dioxane (10 mL), followed by dropwise addition of 4.0 M HCl in dioxane (10 mL) and allowed to stir at RT for 2 h. After completion of reaction, the reaction mixture was concentrated under reduced pressure and washed with diethyl ether to obtain crude which was purified by column chromatography to afford the title compound. LCMS: 512 [M+H]⁺

Step-3: Preparation of (8S,11R,13S,14S,17R)-17-acetyl-11-(4-((6-(2-(2-(2-(4-(2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)ethoxy)ethylamino)-6-oxohexyl)(methyl)amino)phenyl)-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate

To a stirred solution of 6-((4-((8S,11R,13S,14S,17R)-17-acetoxy-17-acetyl-13-methyl-3-oxo-2,3,6,7,8,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-11-yl)phenyl) (methyl)amino)hexanoic acid (0.15 g, 0.26 mmol, 1.0 eq) in DMF (8 mL) was added HATU (0.15 g, 0.39 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.18 mL, 1.04 mmol, 4.0 eq) and 4-(3-(4-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (0.13 g, 0.26 mmol, 0.8 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with water (40 mL), brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure to obtain a crude which was purified by reversed phase HPLC to afford the title compound. LCMS: 1070 [M+H]⁺

¹H NMR (400 MHz, Methanol-d₄) δ 8.37 (dd, J=7.9, 1.6 Hz, 1H), 7.98-7.78 (m, 3H), 7.47 (d, J=6.4 Hz, 1H), 7.38 (t, J=5.5 Hz, 1H), 7.15 (td, J=9.2, 3.8 Hz, 1H), 7.00 (d, J=8.2 Hz, 2H), 6.63 (dd, J=8.6, 4.0 Hz, 2H), 5.74 (s, 1H), 4.61 (s, 1H), 4.45 (d, J=7.1 Hz, 1H), 4.38 (s, 2H), 4.26 (d, J=22.9 Hz, 2H), 3.82-3.70 (m, 2H), 3.69-3.40 (m, 11H), 3.35 (t, J=3.0 Hz, 1H), 3.25 (t, J=7.7 Hz, 3H), 2.82 (dd, J=11.8, 5.3 Hz, 5H), 2.61 (qd, J=14.8, 13.9, 8.7 Hz, 4H), 2.50-1.92 (m, 15H), 1.78 (q, J=7.4, 5.8 Hz, 2H), 1.68-1.27 (m, 9H), 0.33 (s, 4H).

Synthetic Method 13 Example S-8. Preparation of 4-(3-(4-(6-(2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)hexanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (1386)

Step-1: Preparation of (8S,9S,10R,13S,14S,17S)-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of 2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl acetate 19 (1 g, 2.68 mmol) in MeOH (8 mL), and H₂O (8 mL) was added K₂CO₃ (0.37 g, 2.68 mmol) dissolved in H₂O (2 mL) at room temperature, and the reaction was monitored by TLC. After completion of the reaction, solvent was removed under reduced pressure and the reaction mixture was diluted with EtOAc (50 mL) and washed with H₂O (2×20 mL) and brine. The sample was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the title compound. LCMS: 331 [M+H]⁺

Step-2: Preparation of 2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl methanesulfonate

To a stirred solution of (8S,9S,10R,13S,14S,17S)-17-(2-hydroxyacetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (1 g, 3 mmol) in DCM (30 mL) was added triethylamine (2.1 mL, 15 mmol) followed by addition of mesyl chloride (0.65 mL, 7.5 mmol) at 0° C. and the resultant mixture was stirred at RT for 2 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated NaHCO₃ solution. The aqueous layer was then extracted with DCM (30 mL×3). The combined organic layers were washed with water (50 mL), brine (50 mL) dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound which was taken to the next step without further purification. LCMS: 409 [M+H]⁺

Step-3: Preparation of (8S,9S,10R,13S,14S,17S)-17-(2-(6-hydroxyhexyloxy)acetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of hexane-1,6-diol (1.4 g, 12.25 mmol) in THF (20 mL) was successively added NaH (0.25 g, 6.1 mmol, 2.5 eq) portion wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then 2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl methanesulfonate (1 g, 2.45 mmol, 1 eq) and TBAB (0.4 g, 1.22 mmol, 0.5 eq) was added and the resultant mixture was stirred at RT for 2 h. The reaction was monitored by TLC and LC-MS. Upon completion, the mixture was diluted with water (20 mL) and extracted with DCM (30 mL×3). The combined organic layers were washed with brine (20 mL) dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatography to afford the title compound. LCMS: 431 [M+H]⁺

Step-4: Preparation of 6-(2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)hexanoic acid

A solution of (8S,9S,10R,13S,14S,17S)-17-(2-(6-hydroxyhexyloxy)acetyl)-10,13-dimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (0.15 g, 0.34 mmol, 1 eq) in acetone (10 mL) was added Jones reagent (2 mL) at 0° C. dropwise over a period of 20 min. The resultant mixture was stirred at 0° C. for 5 min. The reaction was monitored by TLC. After completion, water (20 mL) was added and extracted with DCM (30 mL×3). The combined organic layers were washed with brine (20 mL) dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain a the title compound which was taken to next step without further purification. LCMS: 445 [M+H]⁺

Step-5: Preparation of 4-(3-(4-(6-(2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)hexanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

To a stirred solution of 6-(2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)hexanoic acid (0.08 g, 0.18 mmol, 1.0 eq) in DMF (5 mL) was added HATU (0.1 mg, 0.27 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.12 mL, 0.72 mmol, 4.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.06 g, 0.16 mmol, 0.9 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered through a Buchner funnel to obtain a crude which was purified by reversed phase HPLC to afford the title compound. LCMS: 794 [M+H]⁺

¹H NMR (400 MHz, Methanol-d₄) δ 8.40-8.33 (m, 1H), 7.99-7.79 (m, 3H), 7.49 (dd, J=9.0, 5.1 Hz, 1H), 7.38 (t, J=6.3 Hz, 1H), 7.16 (t, J=9.0 Hz, 1H), 5.71 (s, 1H), 4.39 (s, 2H), 4.07 (kept, J=5.3 Hz, 2H), 3.83-3.61 (m, 4H), 3.51 (dt, J=15.7, 5.0 Hz, 2H), 3.34 (d, J=8.1 Hz, 1H), 2.65-2.36 (m, 5H), 2.35-2.23 (m, 2H), 2.12-2.01 (m, 1H), 1.95-1.78 (m, 2H), 1.66 (m, 9H), 1.5-0.91 (m, 16H), 0.77 (d, J=6.6 Hz, 3H).

Synthetic Method 14 Example S-9. Preparation of 4-(3-(4-(6-(2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)hexanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (1392)

Step-1: Preparation of 4-(3-(4-(6-(2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)hexanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

To a stirred solution of 6-(2-((8S,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)hexanoic acid (100 mg, 0.22 mmol, 1.0 eq) in DMF (5 mL) was added HATU (125.4 mg, 0.33 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.19 mL, 1.11 mmol, 5.0 eq) and 4-(3-(4-(2-(2-(2-aminoethoxy)ethoxy)acetyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (112 mg, 0.22 mmol, 1 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered over Buchner funnel to obtain a crude which was purified by reversed phase HPLC to afford the title compound. LCMS: 939 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.86 (dt, J=25.1, 7.5 Hz, 3H), 7.44 (ddd, J=8.2, 5.1, 2.3 Hz, 1H), 7.37 (s, 1H), 7.23 (t, J=9.0 Hz, 1H), 5.60 (s, 1H), 4.33 (s, 2H), 4.15 (d, J=22.2 Hz, 2H), 3.93 (ddt, J=39.8, 11.2, 6.1 Hz, 2H), 3.62 (t, J=9.0 Hz, 2H), 3.51 (q, J=12.9, 9.7 Hz, 6H), 3.38 (d, J=8.3 Hz, 2H), 3.22-3.11 (m, 4H), 2.45-2.32 (m, 4H), 2.26-1.18 (m, 19H), 1.11 (d, J=16.0 Hz, 6H), 0.97-0.73 (m, 6H), 0.67 (s, 1H).

Synthetic Method 15 Example S-10. Preparation of 4-(3-(4-(6-4(1S,3aS,3bR,5aS,10aS,10bS,12aS)-10a,12a-dimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl)oxy)hexanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (1394)

Step-1: Preparation of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydrospiro [cyclopenta[a] henanthrene-3,2′-[1,3]dioxolan]-17-ol

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-17-hydroxy-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (10 g, 34.5 mmol) in benzene (300 mL) was added PTSA (3 g, 17.2 mmol, 0.5 eq) followed by addition of ethylene glycol (10.7 g, 172.4 mmol, 5 eq) at RT and the resultant mixture was heated at 120° C. using a Dean-Stark apparatus for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL×2). The organic layer was washed with saturated NaHCO₃ solution (100 mL), water (200 mL), brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound. LCMS: 335 [M+H]⁺

Step-2a: Preparation of 2-(6-chlorohexyloxy)tetrahydro-2H-pyran

To a stirred solution of 6-chlorohexan-1-ol (10 g, 73.16 mmol) in diethyl ether (100 mL) was added PTSA (0.05 g, 0.37 mmol, 0.005 eq) followed by addition of 3,4-dihydro-2H-pyran (8.4 g, 102.5 mmol, 1.4 eq). The resulting reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was diluted with diethyl ether (350 mL). The organic layer was washed with 20% KOH solution (100 mL), water (300 mL), brine (200 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound.

Step-2: Preparation of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-17-(6-(tetrahydro-2H-pyran-2-yloxy)hexyloxy)hexadecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolane]

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydrospiro [cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolan]-17-ol (50 g, 150 mmol) and 2-(6-chlorohexyloxy)tetrahydro-2H-pyran (65.8 g, 300 mol, 2 eq) in xylene (200 mL) was added t-BuONa (28.7 g, 300 mmol, 2 eq) at RT slowly and the resultant mixture was heated to 150° C. for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was cooled to RT, quenched slowly with ice cold water (2000 mL) and extracted with EtOAc (1000 mL×3). The organic layer was washed with water (1000 mL×2), brine (1000 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatography to afford the title compound.

Step-3: Preparation of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyl tetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-17-(6-(tetrahydro-2H-pyran-2-yloxy)hexyloxy)hexadecahydrospiro[cyclopenta[a]phenanthrene-3,2′-[1,3]dioxolane] (1.0 g, 1.9 mmol, 1.0 eq) in THF:H₂O (35:5 mL) was added 6N HCl in 1,4 dioxane (20 mL) at 0° C. and the mixture was stirred at RT for 1 h. The reaction was monitored by TLC. Upon completion, the mixture was under reduced pressure to obtain a crude residue which was triturated using diethyl ether to afford the title compound. LCMS: 391 [M+H]⁺

Step-4: Preparation of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-2-carbaldehyde

To a solution of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyl tetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (1 g, 2.5 mmol) in pyridine (20 mL) was added sodium methoxide (0.27 g, 5.1 mmol) followed by addition of ethyl formate (1.2 g, 16.9 mmol) under nitrogen. The mixture was stirred at RT for 16 h. The reaction was monitored by TLC. After completion, the mixture was quenched with 5% AcOH (150 mL) to obtain a precipitate which was then extracted with DCM (200 mL×3). The combined organic layers were washed with water (200 mL). The combined organic layers were washed with 2% KOH solution (200 mL×2). The aqueous layer was then acidified using AcOH (pH ˜4-5) to obtain a precipitate which was further extracted with DCM (200 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated to afford the title compound. LCMS: 419 [M+H]⁺

Step-5: Preparation of compound 6-(((1S,3aS,3bR,5aS,10aS,10bS,12aS)-10a,12a-dimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl)oxy)hexan-1-ol

To a solution of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthrene-2-carbaldehyde (0.7 g, 1.6 mmol) in 5% AcOH in EtOH (15 mL) was added hydrazine hydrate (0.16 g, 3.3 mmol) and the resultant mixture was heated at 80° C. for 2 h. After completion, the mixture was diluted with ice-cold water (50 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated to afford the desired compound which was taken to next step without further purification. LCMS: 415 [M+H]⁺

Step-6: Preparation of compound 6-(((1S,3aS,3bR,5aS,10aS,10bS,12aS)-10a,12a-dimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl)oxy)hexanoic acid acid

A solution of 6-(((1S,3aS,3bR,5aS,10aS,10bS,12a5)-10a,12a-dimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl)oxy)hexan-1-ol (0.41 g, 1 mmol, 1 eq) in acetone (90 mL) was added Jones reagent (0.6 mL) at 0° C. dropwise over a period of 20 min. The resultant mixture was stirred at 0° C. for 5 min. The reaction was monitored by TLC. After completion, water (200 mL) was added and the resulting precipitate was filtered through a Büchner funnel. The solid obtained was washed with water (50 mL×2) and n-pentane (25 mL×2), dried under vacuum to afford the desired compound which was taken to next step without further purification. LCMS: 429 [M+H]⁺

Step-7: Preparation of 4-(3-(4-(6-(((1S,3aS,3bR,5aS,10aS,10bS,12aS)-10a,12a-dimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl)oxy)hexanoyl)piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

To a stirred solution of 6-(((1S,3aS,3bR,5aS,10aS,10bS,12aS)-10a,12a-dimethyl-1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a-hexadecahydrocyclopenta[5,6]naphtho[1,2-f]indazol-1-yl)oxy)hexanoic acid (0.10 g, 0.233 mmol, 1.0 eq) in DMF (5 mL) were successively added HOBt (0.040 g, 0.27 mmol, 1.2 eq) and EDC.HCl (0.104 g, 0.27 mmol, 1.2 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.60 mL, 069 mmol, 3.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.076 g, 0.20 mmol, 0.9 eq) were then added to the mixture and the resultant mixture was stirred at RT for 16 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered through a Büchner funnel to obtain a crude which was purified by reversed phase HPLC to afford the desired compound. LCMS: 777 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (br. s., 1H), 8.31-8.22 (m, 1H), 8.00-7.93 (m, 1H), 7.93-7.76 (m, 2H), 7.44 (d, J=3.1 Hz, 1H), 7.36 (br. s., 1H), 7.31-7.14 (m, 2H), 4.33 (s, 2H), 3.63-3.51 (m, 6H), 3.25-3.1 (m, 3H) (br. s., 1H), 2.40-2.30 (m, 1H), 2.27 (br. s., 2H), 2.15-1.90 (m, 3H), 1.81 (br. s., 2H), 1.64 (s, 3H), 1.57-1.40 (m, 7H), 1.40-1.27 (m, 4H), 1.27-1.03 (m, 4H), 1.03-0.90 (m, 1H), 0.90-0.74 (m, 3H), 0.73-0.53 (m, 5H).

Synthetic Method 16 Example S-11. Preparation of 4-(4-fluoro-3-(4-(64(2R,5S,8R,9S,10S,13S,14S,17S)-2,10,13-trimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (1402)

Step-1: Preparation of (5S,8R,9S,10S,13S,14S,17S,Z)-17-(6-hydroxyhexyloxy)-2-(hydroxyl methylene)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (2.0 g, 5.12 mmol) in toluene (20 mL) at 0° C. was added NaH (0.82 g, 20.5 mmol) portion wise followed by the addition of ethyl formate (0.57 g, 0.77 mmol). The resultant mixture was stirred at RT for 1 h and then monitored by TLC. After completion, the mixture was filtered through a Büchner funnel. The residue obtained was poured into ice-cold water and the precipitate obtained was again filtered through a Büchner funnel to afford the title compound. LCMS: 419 [M+H]⁺

Step-2: Preparation of (2R,5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-2,10,13-trimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S,Z)-17-(6-hydroxyhexyloxy)-2-(hydroxyl methylene)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (2.0 g, 4.78 mmol) in MeOH (20 mL) was added Pd/C (0.2 g) and the resultant mixture was hydrogenated at RT for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was filtered through a Celite bed and filtrate obtained was concentrated to obtain a crude residue which was purified by CombiFlash chromatography to afford the title compound. LCMS: 405 [M+H]⁺

Step-3: Preparation of 6-((2R,5S,8R,9S,10S,13S,14S,17S)-2,10,13-trimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexanoic acid

A solution of (2R,5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-2,10,13-trimethyl tetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (0.2 g, 0.5 mmol, 1 eq) in acetone (20 mL) was added Jones reagent (0.2 mL) at 0° C. dropwise over a period of 20 min. The resultant mixture was stirred at 0° C. for 5 min. The reaction was monitored by TLC. After completion, water (100 mL) was added and the resulting precipitate was filtered through a Buchner funnel. The solid obtained was washed with water (50 mL×2), n-pentane (50 mL×2) and dried under vacuum to afford the title compound which was taken to next step without further purification. LCMS: 419 [M+H]⁺

Step-4: Preparation of 4-(4-fluoro-3-(4-(64(2R,5S,8R,9S,10S,13S,14S,17S)-2,10,13-trimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexanoyl)piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one

To a stirred solution of 6-((2R,5S,8R,9S,10S,13S,14S,17S)-2,10,13-trimethyl-3-oxohexadeca hydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexanoic acid (0.10 g, 0.23 mmol, 1.0 eq) in DMF (5 mL) was added HATU (0.14 g, 0.35 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.09 g, 0.71 mmol, 3.0 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.09 g, 0.23 mmol, 1 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered through a Buchner funnel to obtain a crude which was purified by CombiFlash chromatography to afford the title compound. LCMS: 767 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 8.26 (d, J=7.9 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.92-7.86 (m, 1H), 7.86-7.78 (m, 1H), 7.50-7.40 (m, 1H), 7.36 (br. s., 1H), 7.24 (t, J=8.8 Hz, 1H), 4.33 (s, 2H), 3.62 (m, 2H), 3.59-3.43 (m, 4H), 3.27-3.04 (m, 4H), 2.43-2.16 (m, 4H), 1.98-1.85 (m, 4H), 1.77 (m, 2H), 1.60 (d, J=13.2 Hz, 2H), 1.54-1.41 (m, 6H), 1.41-1.14 (m, 12H), 1.02 (s, 2H), 0.86 (d, J=6.1 Hz, 3H), 0.68 (d, J=7.0 Hz, 3H)

Synthetic Method 17 Example S-12. Preparation of 4-(3-(4-(6-((5S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-17-yloxy)hexanoyl) piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (1410)

Step-1: Preparation of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-17-hydroxy-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (2.0 g, 6.9 mmol) in DCM (20 mL) at 0° C. was added TEA (2.8 g, 20.6 mmol) then acetyl chloride (0.81 g, 10.3 mmol) dropwise and the reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure. The residue obtained was diluted with DCM (200 mL), washed with H₂O (200 mL×2), brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash chromatography to afford the title compound. LCMS: 333 [M+H]⁺

Step-2: Preparation of (5S,8R,9S,10S,13S,14S,17S)-2-bromo-10,13-dimethyl-3-oxohexadeca hydro-JH-cyclopenta[a]phenanthren-17-yl acetate

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl acetate (0.6 g, 1.80 mmol) in AcOH (6 mL) at 0° C. were added catalytic amount HCl (1 drop) and bromine (0.1 g, 6.02 mmol) slowly and the resultant mixture was stirred at RT for 1 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was quenched with saturated NaHCO₃ solution. The precipitate obtained was filtered through a Büchner funnel and dried under vacuum to afford the title compound. LCMS: 411 [M+H]^(+±,) 413 [M+H+2]⁺

Step-3: Preparation of (5S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-17-yl acetate

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-2-bromo-10,13-dimethyl-3-oxohexadeca hydro-1H-cyclopenta[a]phenanthren-17-yl acetate (0.72 g, 1.75 mmol) in DMF (40 mL) were added LiBr (0.35 g, 4.04 mmol) and Li₂CO₃ (0.35 g, 4.74 mmol, 2.7 eq) and the resultant mixture was heated at 150° C. for 2 h. The reaction was monitored by TLC and LC-MS. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatography to afford the title compound. LCMS: 331 [M+H]⁺

Step-4: Preparation of (5S,8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

To a stirred solution of (5S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-17-yl acetate (0.3 g, 0.90 mmol) in MeOH (5 mL) was added KOH (0.15 g, 2.72 mmol, 3 eq) and the mixture was stirred at RT for 1 h. The reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure and the residue obtained was dissolved in water (15 mL) and acidified using AcOH (pH ˜7). The precipitate was filtered through a Büchner funnel, washed with H₂O (2×10 mL) and n-hexane (10 mL) to afford the title compound. LCMS: 289 [M+H]⁺

Step-5: Preparation of (5S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-17-(6-(tetrahydro-2H-pyran-2-yloxy)hexyloxy)-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

A solution of (5S,8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.35 g, 1.05 mmol, 1 eq) in DMF (10 mL) at 0° C. was added NaH (0.42 g, 10.5 mmol, 10 eq) portion wise over a period of 10 min and the mixture was stirred at 0° C. for 15 min. 2-(6-bromohexyloxy)tetrahydro-2H-pyran (1.38 g, 5.28 mmol, 5 eq) was then added to the mixture and the mixture was stirred at RT for 4 h. The reaction was monitored by TLC. After completion, the mixture was quenched by ice-cold water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash chromatography to afford the title compound. LCMS: 473 [M+H]⁺

Step-6: Preparation of (5S,8R,9S,10R,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one

To a stirred solution of (5S,8R,95,10R,13S,14S,17S)-10,13-dimethyl-17-(6-(tetrahydro-2H-pyran-2-yloxy)hexyloxy)-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.35 g, 0.74 mmol, 1.0 eq) in THF:H₂O (3:1) was added 4N HCl in 1,4 dioxane (2 mL) at 0° C. and the mixture was stirred at RT for 1 h. The reaction was monitored by TLC. Upon completion, the mixture was concentrated under reduced pressure to obtain a crude residue which was triturated using diethyl ether to afford the title compound. LCMS: 389 [M+H]⁺

Step-7: Preparation of 6-((5S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-17-yloxy)hexanoic acid

A solution of (5S,8R,9S,10R,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyl-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one (0.17 g, 0.7 mmol, 1 eq) in acetone (8 mL) at 0° C. was added Jones reagent (0.4 mL) dropwise over a period of 20 min. The resultant mixture was stirred at 0° C. for 5 min. The reaction was monitored by TLC. After completion, water (200 mL) was added and the resulting precipitate was filtered through a Büchner funnel. The solid obtained was washed with water (50 mL×2), n-pentane (25 mL×2), dried under vacuum to afford the title compound which was taken to next step without further purification. LCMS: 403 [M+H]⁺

Step-8: Preparation of 4-(3-(4-(6-((5S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-17-yloxy)hexanoyl) piperazine-1-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one

To a stirred solution of 6-((5S,8R,9S,10R,13S,14S,17S)-10,13-dimethyl-3-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-17-yloxy)hexanoic acid (0.08 g, 0.2 mmol, 1.0 eq) in DMF (8 mL) was added HATU (0.12 g, 0.3 mmol, 1.5 eq) at 0° C. and the mixture was stirred at the same temperature for 20 min. DIPEA (0.07 g, 0.6 mmol, 3 eq) and 4-(4-fluoro-3-(piperazine-1-carbonyl)benzyl)phthalazin-1(2H)-one (0.09 g, 0.24 mmol, 1.2 eq) were then successively added to the mixture and the resultant mixture was stirred at RT for 2 h. The progress of reaction was monitored by LC-MS. Upon completion, the mixture was poured into ice cold water (50 mL) and resulting precipitate was filtered through a Büchner funnel to obtain a crude which was purified by reversed phase HPLC to afford the title compound. LCMS: 751 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.60 (s, 1H), 8.35-8.19 (m, 1H), 7.99-7.76 (m, 2H), 7.62-7.39 (m, 1H), 7.36 (br. s., 1H), 7.30-7.13 (m, 2H), 5.74 (d, J=10.1 Hz, 1H), 4.33 (s, 2H), 3.62 (br. s., 2H), 3.59-3.41 (m, 2H), 3.31-3.25 (m, 2H), 3.28-3.21 (m, 1H), 3.14 (s, 2H), 3.18 (s, 1H), 2.67 (br. s., 2H), 2.48-2.22 (m, 4H), 2.16-1.94 (m, 2H), 1.94-1.70 (m, 4H), 1.61 (d, J=13.2 Hz, 2H), 1.52-1.27 (m, 7H), 1.26-1.08 (m, 6H), 1.06-0.82 (m, 4H), 0.70 (d, J=7.0 Hz, 3H).

Synthetic Method 18 Example S-13. Preparation of 4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-(6-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamido)hexyl)benzamideN-(6-((5R,8S,9R,10R,13R,14R,17R)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide (1426)

Step-1: Preparation of 6-((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexyl methanesulfonate

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-17-(6-hydroxyhexyloxy)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (0.5 g, 1.2 mmol, 1.0 eq) in DCM (10 mL) was added TEA (0.35 mL, 2.56 mmol, 2.0 eq) followed by methanesulfonyl chloride (0.19 mL, 1.53 mmol, 1.2 eq) at RT and stirred for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was poured onto ice cold water (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and evaporated to afford the title compound. LCMS: 469 [M+H]⁺

Step-2: Preparation of (5S,8R,9S,10S,13S,14S,17S)-17-(6-azidohexyloxy)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of 6-((5S,8R,9S,10S,13S,14S,17S)-10,13-dimethyl-3-oxohexadecahydro-1H cyclopenta[a]phenanthren-17-yloxy)hexyl methanesulfonate (0.3 g, 0.64 mmol, 1.0 eq) in DMF (10 mL) was added NaN₃ (0.07 g, 1.28 mmol, 2.0 eq) at RT and stirred for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was poured onto ice cold water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and evaporated to afford the title compound. LCMS: 416 [M+H]⁺

Step-3: Preparation of (5S,8R,9S,10S,13S,14S,17S)-17-(6-azidohexyloxy)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one

To a stirred solution of (5S,8R,9S,10S,13S,14S,17S)-17-(6-azidohexyloxy)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (0.28 g, 0.67 mmol, 1.0 eq) in THF:H₂O (8:2 mL) was added TPP (0.35 g, 1.34 mmol, 2.0 eq) at RT and stirred for 16 h. The reaction was monitored by TLC. Upon completion, the mixture was filtered, added ice cold water (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine solution (30 mL), dried over Na₂SO₄, filtered and evaporated to afford the title compound. LCMS: 390 [M+H]⁺

Step-4: N-(6-((5R,8S,9R,10R,13R,14R,17R)-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yloxy)hexyl)-2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide

2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (0.23 g, 0.77 mmol, 1.0 eq) was taken in DMF (5 mL). HATU (0.44 g, 1.15 mmol, 1.5 eq) was added and the reaction mixture was stirred at RT for 1 h, followed by addition of (5S,8R,9S,10S,13S,14S,17S)-17-(6-aminohexyloxy)-10,13-dimethyltetradecahydro-1H-cyclopenta[a]phenanthren-3(2H)-one (0.3 g, 0.77 mmol, 1.0 eq) and DIPEA (0.4 mL, 2.31 mmol, 3.0 eq). The reaction mixture was stirred at RT for 2h. The reaction was monitored by TLC. Upon completion, the mixture was poured onto ice cold water. The precipitate formed was collected by filtration and purified by flash column followed by prep HPLC to get title compound. LCMS: 670 [M+H]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 8.20-8.28 (m, 2H), 7.97 (d, J=7.9 Hz, 1H), 7.89 (t, J=6.8 Hz, 1H), 7.79-7.86 (m, 1H), 7.53 (d, J=6.6 Hz, 1H), 7.43 (br. s., 1H), 7.15-7.23 (m, 1H), 4.32 (s, 2H), 3.14-3.26 (m, 4H), 2.27 (d, J=14.5 Hz, 1H), 2.01-2.12 (m, 2H), 1.88 (d, J=12.3 Hz, 3H), 1.77 (d, J=12.3 Hz, 1H), 1.59 (d, J=10.1 Hz, 1H), 1.46 (br. s., 6H), 1.29 (br. s., 7H), 1.23 (br. s., 4H), 1.11-1.20 (m, 2H), 0.95 (s, 3H), 0.88 (d, J=11.0 Hz, 2H), 0.67 (s, 3H).

Biological Assays Biological Example 1

The following methods are for evaluating the in vitro biology properties of the test articles.

a. RBC HotSpot Poly(ADP-ribose) Polymerases 1 (PARP1) and Poly(ADP-ribose) Polymerases 2 (PARP2) Assays: The assay was conducted at Reaction Biology Corporation (RBC; Malvern, Pa.). The assay principle is radioisotope-based filter binding assay where incorporation of radioisotope-labeled NAD into the substrate captured on filter is detected after washout free NAD⁺. Data were analyzed using Excel and GraphPad Prism software for IC₅₀ curve fits. Each assay was conducted with PJ34 as a positive control. Results are listed in Table 5 and Table 9.

-   -   i. PARP1 assay: Human recombinant PARP1 at a final concentration         of 2.5 nM was combined with histone H4 (20 μM) and test articles         at various concentrations in reaction buffer (50 mM Tris-HCL, pH         8.0, 50 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1% DMSO, and 20 μg/mL         activated DNA). The solution was inoculated for 20 min at room         temperature and the reaction initiated by adding         [adenylate-³²P]-Nicotinamide Adenine Dinucleotide, ³²P-NAD⁺ at a         final concentration of 10 μM. After incubation for 2 hrs at room         temperature, the reaction mixture was filtered and washed with         0.75% phosphoric acid for radioactivity detection.     -   ii. PARP2 assay: Human recombinant PARP2 at a final         concentration of 2.5 nM was combined with histone H3 (20 μM) and         test articles at various concentrations in reaction buffer (50         mM Tris-HCL, pH 8.0, 50 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1% DMSO,         and 20 μg/mL activated DNA). The solution was inoculated for 20         min at room temperature and the reaction was initiated by adding         [adenylate-³²P]-Nicotinamide Adenine Dinucleotide, ³²P-NAD⁺ at a         final concentration of 10 μM. After incubation for 2 hrs at room         temperature, the reaction mixture was filtered and washed with         0.75% phosphoric acid for radioactivity detection.         b. AR binding assay: AR in LNCaP cytosol was used for         determining the binding affinity of test articles and the         reference compound-progesterone (Sigma, Cat: E2785, St. Louis,         Mo.). IC₅₀s were determined using 8 concentrations/compound.         Cytosol is plated at 200 μg/well (100 μL) into a 96-well conical         polypropylene plate (Agilent, Cat: 5042-1385, Santa Clara,         Calif.) and mixed with 3 μL of test compound. After adding 100         μL of ³H-methyltrienolone (PerkinElmer, Cat: NET590250UC, San         Jose, Calif.), the plate was sealed and shaken at 300 rpm at         4° C. for 24 hours. Post incubation, 100 μL of radioligand         adsorption buffer containing 10 mM Tris-HCl, pH 7.4; 1.5 mM         EDTA; 1 mM DTT; 0.25% charcoal; 0.0025% dextran was added to         individual wells. Plate was shaken for 15 mM at 4° C. followed         by centrifugation at 3000 rpm for 30 min at 4° C. 150 μL of         supernatant is transferred into scint-tube (PerkinElmer,         Cat: 6000192) and mixed with 2 mL of Ultima Gold Cocktail         (PerkinElmer, Cat: 6013329). Radioactivity is counted using a         TriCarb 2910 TR scintillation counter (PerkinElmer). Inhibition         of the radioactivity by test articles was calculated using the         equation below:

% Inhibition=(1−(Assay well-Average_LC)/(Average_HC-Average_LC))×100%.

IC₅₀ values (Table 6) were calculated and graphed using the model “log(inhibitor) vs. response—Variable slope” included in GraphPad Prism 5 (San Diego, Calif.). The Ki values were further calculated using the equation below where [L] is the radioligand concentration (1 nM) used in this study. Kd value was 0.332 nM.

Ki=IC₅₀/(1+[L]/Kd)

c. AR transactivation: Human AR cloned into a CMV vector backbone is used for the transactivation study. HEK-293 cells are plated at 80,000 cells per well of a 24 well plate in DME+5% csFBS. Twenty four hours later, the cells are transfected using Lipofectamine (Invitrogen, Carlsbad, Calif.) with 0.25 μg GRE-LUC, 0.01 μg CMV-LUC (renilla luciferase) and 25 ng of the AR in OPTIMEM medium. The cells are treated 24 hrs after transfection with various ligands (10⁻¹² to 10⁻⁵ M final concentrations) and luciferase assay performed 48 hours after transfection. Firefly values are normalized to renilla luciferase values and the values represented as relative light units (RLU). Agonist and antagonist assays for the test article are performed in the absence and in the combination with 0.1 nM R1881, respectively. Data are represented as EC₅₀ (for agonists) and IC₅₀ (for antagonists) values obtained from four parameter logistics curve. d. Cell culture and proliferation assays: 22RV1 and HT-29 cells are procured from American Type Culture Collection (ATCC). Cells are cultured in medium recommended by the ATCC. Cell culture medium is obtained from Fisher scientific (Waltham, Mass.) and serum is obtained from Hyclone (San Angelo, Tex.).

Cells are plated at varying density in the respective growth medium in 96 well plates. 24 hr later, cells are treated, in triplicate or quadruplicate, with test articles prepared in a range of concentrations by series dilution of DMSO stock solutions in growth medium and incubated for three to seven days. The number of viable 22RV1 and HT-29 cells is measured using CellTiter Glo assay (CTG, Promega, Madison, Wis.) after three days of treatment. Cell viability data are plotted using GraphPad Prism (GraphPad Software, Inc., San Diego, Calif.). In addition, a nonlinear regression model with a sigmoidal dose response and variable slope within GraphPad Prism is used to calculate the IC₅₀ value of individual test articles.

e. Additional cell proliferation assays: Other cancer cell lines can be tested in a cell proliferation assays. For example, LnCaP, PC-3, MCF-7, HCC1428, BT474, HCT-116, SK-OV-3 or OVCAR3 cancer cells are tested. Cells are cultured in medium recommended by the supplier (e.g., ATCC or JCRB Cell Bank), at 37° C. in a 5% CO₂ environment. For the proliferation assay, cells are plated in the growth medium in 96 well plates. Seeding density is adjusted according to the cell type. 24 hr later, cells are treated, in triplicate or quadruplicate, with test articles prepared in a range of concentrations by series dilution of DMSO stock solutions in growth medium, and typically incubated for three to seven days, with test article-containing medium replaced after three or four days. The number of viable cells is measured using CellTiter Glo assay (CTG, Promega, Madison, Wis.) or similar. Cell viability data are plotted using GraphPad Prism (GraphPad Software, Inc., San Diego, Calif.). In addition, a nonlinear regression model with a sigmoidal dose response and variable slope within GraphPad Prism is used to calculate the IC₅₀ value of individual test articles. Similarly, HEK-293 and HeLa calls can also be tested by methods known in the art. f. Nuclear translocation: LNCaP cells are plated on coverslips in 24 well plates in growth medium. Twenty-four hours after plating, medium is changed to RPMI+1% csFBS and the cells are maintained in this medium for two days. Medium is replaced again and the cells are treated. Cells are fixed 4 hours after treatment and the AR immunostained using AR N20 antibody (Santa Cruz Biotechnology, Santa Cruz, Calif.). Nucleus is stained with DAPI. Cells are imaged with a confocal microscope. g. ER binding assay: ERα binding is assessed by the LanthaScreen® TR-FRET ER Alpha Competitive Binding Assay at Thermo Fisher. In this assay, a terbium-labeled anti-GST antibody is used to indirectly label GST-tagged ER Alpha-ligand binding domain (LBD) by binding to its GST tag. Competitive binding to the ER Alpha-LBD (GST) is detected by a test compound's ability to displace a fluorescent ligand (Fluormone™ ES2 Green tracer) from the ER Alpha-LBD (GST), which results in a loss of FRET signal between the Tb-anti-GST antibody and the tracer. When running the assay, Fluormone™ ES2 Green tracer is added to ligand test compounds or solvent controls followed by addition of a mixture of the ER Alpha-LBD (GST) and terbium anti-GST antibody. After an incubation period at room temperature, the TR-FRET ratio of 520:495 emissions are calculated and used to determine the IC₅₀ from a dose response curve of the compound. h. ER and PR functional assays: COS cells are transfected with 25 ng rat progesterone receptor (PR) and 250 ng GRE-LUC or 50 ng human estrogen receptor α (ER) and 250 ng ERE-LUC. Cells are also transfected with 10 ng CMV-renilla LUC in OptiMEM medium using lipofectamine transfection reagent. Twenty-four hours after transfection medium is changed to DME+5% csFBS w/o and treated with compounds in the presence of 0.1 nM progesterone for PR and estradiol for ER. Twenty four hours after treatment, cells are harvested and luciferase assay is performed using dual luciferase assay kit. The firefly values are normalized to renilla luciferase values and represented as a ratio. i. Evaluation of test compound in mouse xenograft model: To examine the in vivo antitumor activity of test compound, tumor growth experiments are performed in a cell line xenograft model. Male NOD SCID Gamma (NSG) mice are housed as five animals per cage and are allowed free access to water and commercial rodent chow. 22RV1 cells (grown in RPMI+10% FBS) mixed with 50% matrigel basement membrane are implanted subcutaneously in castrated mice. Alternatively, an antiandrogen resistant cell line other than 22RV1, such as MR49F or VCaP, is used. Once the tumors reach 200-500 mm³, the animals are randomized and treated intraperitoneally with vehicle (DMSO:PEG-300:corn oil 10:30:60 ratio) or test compound. Tumors are measured thrice weekly and the volume is calculated using the formula length*width*width*0.5 Animals are sacrificed at the end of 28 days of treatment and the tumors are weighed and stored for further processing. The tumor growth inhibition (TGI) is calculated by comparing the control group's tumor measurements with the other study groups. TGI is calculated for each group using the formula listed below:

TGI (%)=[1−(TV_(Treatment_DayN)−TV_(Treatment_Day0))/(TV_(Vehicle_DayN)−TV_(Vehicle_Day0))]×100%

TV_(Treatment_DayN) is the average tumor volume of a treatment group on a given day, TV_(Treatment_Day0) is the average tumor volume of the treatment group on the first day of treatment, TV_(Vehicle_DayN) is the average tumor volume of the vehicle control group on a given day, and TV_(Vehicle_Day0) is the average tumor volume of the vehicle group on the first day of treatment. j. DNA-PK Inhibition: Inhibition of DNA-PK activity by test compounds is assessed in a radioisotope-based filter binding assay (Reaction Biology Corporation HotSpot Kinase Assay) as follows. Test compounds are dissolved in 100% DMSO to specific concentrations. Serial dilution of the test compounds are conducted by Integra Viaflo Assist in DMSO. The substrate, DNA-PKtide (Anaspec, Fremont, Calif.; #60210-5), is prepared in Reaction Buffer (20 mM Hepes (pH 7.5), 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na₃VO4, 2 mM DTT, 1% DMSO) so that its final concentration in the reaction would be 20 μM. DNA-PK activator containing dsDNA is delivered to the solution (10 μg/mL in final reaction). DNA-PK (Invitrogen, Carlsbad, Calif.; #PR9107A) is delivered to the substrate solution (5 nM in final reaction) and the solution gently mixed. Compounds in 100% DMSO are delivered into the kinase reaction mixture by Acoustic technology (Echo550; nanoliter range), and the reaction incubated for 20 min at room temperature. ³³P-ATP (Specific activity 10 μCi/μL) is delivered into the reaction mixture to initiate the reaction, which is incubated for 2 hours at room temperature. Radioactivity is detected by a filter-binding method. Kinase activity data are expressed as the percent remaining kinase activity in test samples compared to vehicle (dimethyl sulfoxide) reactions. IC₅₀ values and curve fits are obtained using GraphPad Prism.

TABLE 5 In vitro results PARP1 IC₅₀ PARP2 IC₅₀ Compound No. (μM) (μM) 1128 0.252 0.014

TABLE 6 In vitro NHR binding Compound No. AR K_(i) (μM) 1128 >7.47

Biological Example 2

AR binding assay: To assess AR binding, test compound (top dose 10 μM, 4 fold serial dilution, 8 point dose response) and control (progesterone) were transferred to the assay plate. Cytosol from LnCaP cells was added to the plate, followed by addition of radiolabeled ³H-R1881 at a final concentration of 1 nM. The plate was sealed, and the reaction was incubated at 300 rpm at 4° C. for 24 hrs. Radioligand absorption buffer (10 mM Tris-HCl, pH 7.4; 1.5 mM EDTA; 1 mM DTT; 0.25% charcoal; 0.0025% dextran) was then added to the plate, mixed, and incubated at 4° C. for 15 minutes. The plate was then centrifuged at 3000 rpm for 30 minutes at 4° C. The supernatant was transferred to the scint-tube and Tri-carb was used for scintillation counting. The data was analyzed using GraphPadPrism v5.0 and binding IC₅₀ was determined as the concentration where 50% inhibition of radioligand binding was observed.

GR binding assay: To assess GR binding, test compound (top dose 1 μM, 4 fold serial dilution, 8 point dose response) and control (dexamethasone) were transferred to the assay plate. Cytosol from IM-9 cells was added to the plate, followed by addition of radiolabeled ³H-Dexamethasone at a final concentration of 1.5 nM. The plate was sealed, and the reaction was incubated at 300 rpm at 4° C. for 24 hrs. Radioligand absorption buffer (10 mM Tris-HCl, pH 7.4; 1.5 mM EDTA; 1 mM DTT; 0.25% charcoal; 0.0025% dextran) was then added to the plate, mixed, and incubated at 4° C. for 15 minutes. The plate was then centrifuged at 3000 pm for 30 minutes at 4° C. The supernatant was transferred to the scint-tube and Tri-carb was used for scintillation counting. The data was analyzed using GraphPadPrism v5.0 and binding IC50 was determined as the concentration where 50% inhibition of radioligand binding was observed.

PR binding assay: Progesterone PR-B receptors from human breast carcinoma T47D cells are used in modified Na₂HPO₄/NaH₂PO₄ buffer pH 7.4. Compounds were screened at a range of doses (Top dose 40 nM, 4 fold serial dilution, 8 point dose response) and were dispensed into the assay plate. Supernatant of 1.2×10⁵ cells aliquot was added to the assay plate and was incubated with 0.5 nM [³H]Progesterone for 20 hours at 4° C. Membranes are filtered and washed, the filters are then counted to determine [³H]Progesterone specifically bound. Binding IC₅₀ was determined as the concentration where 50% inhibition of radioligand binding was observed.

AR antagonism assay: To evaluate AR antagonist activity, test compound was added to the assay plate (top dose 10 μM, 3 fold serial dilution, 10 point dose response). HEK293 cells stably expressing the full-length androgen receptor were seeded at a density of 20000 cells/well in the assay plate. The assay plate was then incubated at room temperature for 10 minutes and at 37° C., 5% CO₂ for 20 minutes. Testosterone was added to the assay plate at 1 nM final concentration and the assay plate was incubated at 37° C., 5% CO₂ for 20 h. After the incubation period, Steady-glo was added to the assay plate and mixed at room temperature for 20 minutes on an orbital shaker, before reading out on the EnVision plate reader.

GR antagonism assay: To evaluate GR antagonist activity, test compound was added to the assay plate (top dose 5 μM, 4 fold serial dilution, 8 point dose response). HEK293 cells stably expressing the ligand binding domain of the glucocorticoid receptor were seeded at a density of 40000 cells/well in the assay plate. The assay plate was then incubated at 37° C., 5% CO₂ for 30 minutes. Dexamethasone was added to the assay plate at 1.5 nM final concentration and the assay plate was incubated at 37° C., 5% CO₂ for 20 h. After the incubation period, Dual-glo luciferase reagent was added to the assay plate and mixed at room temperature for 20 minutes on an orbital shaker, before reading out on the EnVision plate reader.

PR coactivator antagonist assay: Test compound (Top dose 10 μM, 4 fold serial dilution, 8 point dose response) and/or vehicle was incubated with the 2.5 nM Progesterone Receptor (PR)-LBD and coactivator peptide for 30 minutes at RT. Determination of the amount of complex formed is read spectrofluorimetrically (excitation: 337 nm, emission: 520/490 nm). Test compound-induced inhibition of 10 nM progesterone-induced fluorescence response by 50 percent or more (50%) indicates receptor antagonist activity.

Cell viability assay: LNCap, 22Rv1, and T47D cells were seeded at a density of 1500-2000 cells/well in 96 well plates, and a ‘TO’ (timepoint 0) was included along with the assay plate. The plates were then incubated at 37° C., 5% CO₂ in a cell culture incubator overnight. On the next day, the ‘TO’ plate was assayed using CellTiterGlo (Promega, Inc) according to the manufacturer's instructions. The appropriate compounds were diluted in DMSO and added to the assay plate (final DMSO concentration of 0.2%) on the next day. The assay plates were incubated for 6 days at 37° C., 5% CO₂. After the incubation period, the plates were assayed using CellTiterGlo (Promega, Inc) according to the manufacturer's instructions and luminescence was read on the EnVision plate reader. Inhibition the tested compounds was determined by the following formula: Inhibition rate (%)=(1−(RLU compound−RLU day0)/(RLU control−RLU day0))*100%. GraphPadPrism was used to analyze the data and determine absolute IC₅₀ values.

Data obtained for certain compounds disclosed herein in the assays described above are shown in Tables 7 and 8.

In Tables 7 and 8 below, activity is provided as follows: A=IC₅₀≤10 nM; B=IC₅₀>10 nM to ≤100 nM; C=IC₅₀ from >100 nM to ≤1,000 nM; D=IC₅₀ from >1,000 nM to ≤10,000 nM; E=IC₅₀>10,000 nM; NT=Not tested.

TABLE 7 AR AR No. binding antagonism LNCap 22RV1 1410 B C C C 1402 NT NT NT NT 1394 C D C C 1426 C C D D 138 B C C C 1370 NT NT C C 1128 D D C D

TABLE 8 PR PR AR AR GR GR No. binding antagonism binding antagonism binding antagonism LNCap T47D 1386 B E B C C C C C 1384 A A A E A B D D 1378 A A A C A A C C 1429 A A B E A B E E 135 A A B C A A C C 1392 NT NT NT NT NT NT D NT

PARP1 and PARP2 data in Table 9 was obtained as described in the RBC HotSpot Poly(ADP-ribose) Polymerases 1 (PARP1) and Poly(ADP-ribose) Polymerases 2 (PARP2) Assays described above in Biological Example 1. In Table 9 below, activity is provided as follows: A=IC₅₀≤1 nM; B=IC₅₀ from >1 nM to ≤10 nM; C=IC₅₀ from >10 nM to ≤100 nM; C=IC₅₀>100.

TABLE 9 No. PARP1 PARP2 1402 C B 1394 C B 1426 D B 138 A A 1370 A A 1386 B A 1384 B A 1378 B A 1429 A A 135 B A 1392 B A 

1. A compound of Formula A-L-B, wherein: A is A1, A2, A3, or A4, wherein: A1 is

A2 is

A3 is

 and A4 is

L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L45, or L46, wherein: L1 is

L2 is

L3 is

L4 is

L5 is

L6 is

L7 is

L8 is

L9 is

L10 is

L11 is

L12 is

L13 is

L14 is

L15 is

L16 is

L17 is

L18 is

L19 is

L20 is

L21 is

L22 is

L23 is

L24 is

L25 is

L26 is

L27 is

L28 is

L29 is

L30 is

L31 is

L32 is

L33 is

L34 is

L35 is

L36 is

L37 is

L38 is

L39 is

L40 is

L41 is

L42 is

L43 is

L44 is

L45 is

and L46 is

and; B is B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, or B19, wherein: B1 is

B2 is

B3 is

B4 is

B5 is

B6 is

B7 is

B8 is

B9 is

B10 is

B11 is

B12 is

B13 is

B14 is

B15 is

B16 is

B17 is

B18 is

and B19 is

and further wherein the “*” in each A and L moiety denotes a covalent bond therebetween, and the wavy line in each L and B denotes a covalent bond therebetween; wherein the compound of Formula A-L-B is selected from: A1-L1-B1 A1-L1-B2 A1-L1-B3 A1-L1-B4 A1-L1-B5 A1-L1-B6 A1-L1-B7 A1-L1-B8 A1-L1-B9 A1-L1-B10 A1-L1-B11 A1-L1-B12 A1-L1-B13 A1-L2-B1 A1-L2-B2 A1-L2-B3 A1-L2-B4 A1-L2-B5 A1-L2-B6 A1-L2-B7 A1-L2-B8 A1-L2-B9 A1-L2-B10 A1-L2-B11 A1-L2-B12 A1-L2-B13 A1-L3-B1 A1-L3-B2 A1-L3-B3 A1-L3-B4 A1-L3-B5 A1-L3-B6 A1-L3-B7 A1-L3-B8 A1-L3-B9 A1-L3-B10 A1-L3-B11 A1-L3-B12 A1-L3-B13 A1-L4-B1 A1-L4-B2 A1-L4-B3 A1-L4-B4 A1-L4-B5 A1-L4-B6 A1-L4-B7 A1-L4-B8 A1-L4-B9 A1-L4-B10 A1-L4-B11 A1-L4-B12 A1-L4-B13 A1-L5-B1 A1-L5-B2 A1-L5-B3 A1-L5-B4 A1-L5-B5 A1-L5-B6 A1-L5-B7 A1-L5-B8 A1-L5-B9 A1-L5-B10 A1-L5-B11 A1-L5-B12 A1-L5-B13 A1-L6-B1 A1-L6-B2 A1-L6-B3 A1-L6-B4 A1-L6-B5 A1-L6-B6 A1-L6-B7 A1-L6-B8 A1-L6-B9 A1-L6-B10 A1-L6-B11 A1-L6-B12 A1-L6-B13 A1-L7-B1 A1-L7-B2 A1-L7-B3 A1-L7-B4 A1-L7-B5 A1-L7-B6 A1-L7-B7 A1-L7-B8 A1-L7-B9 A1-L7-B10 A1-L7-B11 A1-L7-B12 A1-L7-B13 A1-L8-B1 A1-L8-B2 A1-L8-B3 A1-L8-B4 A1-L8-B5 A1-L8-B6 A1-L8-B7 A1-L8-B8 A1-L8-B9 A1-L8-B10 A1-L8-B11 A1-L8-B12 A1-L8-B13 A1-L9-B1 A1-L9-B2 A1-L9-B3 A1-L9-B7 A1-L9-B8 A1-L9-B9 A1-L9-B11 A1-L9-B13 A1-L20-B1 A1-L20-B2 A1-L20-B3 A1-L20-B4 A1-L20-B5 A1-L20-B6 A1-L20-B7 A1-L20-B8 A1-L20-B9 A1-L20-B10 A1-L20-B11 A1-L20-B12 A1-L20-B13 A1-L21-B1 A1-L21-B2 A1-L21-B3 A1-L21-B4 A1-L21-B5 A1-L21-B6 A1-L21-B7 A1-L21-B8 A1-L21-B9 A1-L21-B10 A1-L21-B11 A1-L21-B12 A1-L21-B13 A1-L22-B1 A1-L22-B2 A1-L22-B3 A1-L22-B4 A1-L22-B5 A1-L22-B6 A1-L22-B7 A1-L22-B8 A1-L22-B9 A1-L22-B10 A1-L22-B11 A1-L22-B12 A1-L22-B13 A1-L23-B1 A1-L23-B2 A1-L23-B3 A1-L23-B4 A1-L23-B5 A1-L23-B6 A1-L23-B7 A1-L23-B8 A1-L23-B9 A1-L23-B10 A1-L23-B11 A1-L23-B12 A1-L23-B13 A1-L24-B1 A1-L24-B2 A1-L24-B3 A1-L24-B4 A1-L24-B5 A1-L24-B6 A1-L24-B7 A1-L24-B8 A1-L24-B9 A1-L24-B10 A1-L24-B11 A1-L24-B12 A1-L24-B13 A1-L30-B1 A1-L30-B2 A1-L30-B3 A1-L30-B4 A1-L30-B5 A1-L30-B6 A1-L30-B7 A1-L30-B8 A1-L30-B9 A1-L30-B10 A1-L30-B11 A1-L30-B12 A1-L30-B13 A1-L31-B1 A1-L31-B2 A1-L31-B3 A1-L31-B4 A1-L31-B5 A1-L31-B6 A1-L31-B7 A1-L31-B8 A1-L31-B9 A1-L31-B10 A1-L31-B11 A1-L31-B12 A1-L31-B13 A1-L32-B1 A1-L32-B2 A1-L32-B3 A1-L32-B7 A1-L32-B8 A1-L32-B9 A1-L32-B11 A1-L32-B13 A1-L39-B1 A1-L39-B2 A1-L39-B3 A1-L39-B4 A1-L39-B5 A1-L39-B6 A1-L39-B7 A1-L39-B8 A1-L39-B9 A1-L39-B10 A1-L39-B11 A1-L39-B12 A1-L39-B13 A1-L40-B1 A1-L40-B2 A1-L40-B3 A1-L40-B4 A1-L40-B5 A1-L40-B6 A1-L40-B7 A1-L40-B8 A1-L40-B9 A1-L40-B10 A1-L40-B11 A1-L40-B12 A1-L40-B13 A1-L41-B1 A1-L41-B2 A1-L41-B3 A1-L41-B4 A1-L41-B5 A1-L41-B6 A1-L41-B7 A1-L41-B8 A1-L41-B9 A1-L41-B10 A1-L41-B11 A1-L41-B12 A1-L41-B13 A1-L42-B1 A1-L42-B2 A1-L42-B3 A1-L42-B4 A1-L42-B5 A1-L42-B6 A1-L42-B7 A1-L42-B8 A1-L42-B9 A1-L42-B10 A1-L42-B11 A1-L42-B12 A1-L42-B13 A1-L43-B1 A1-L43-B2 A1-L43-B3 A1-L43-B4 A1-L43-B5 A1-L43-B6 A1-L43-B7 A1-L43-B8 A1-L43-B9 A1-L43-B10 A1-L43-B11 A1-L43-B12 A1-L43-B13 A1-L44-B1 A1-L44-B2 A1-L44-B3 A1-L44-B7 A1-L44-B8 A1-L44-B9 A1-L44-B11 A1-L44-B13 A2-L1-B1 A2-L1-B2 A2-L1-B3 A2-L1-B4 A2-L1-B5 A2-L1-B6 A2-L1-B7 A2-L1-B8 A2-L1-B9 A2-L1-B10 A2-L1-B11 A2-L1-B12 A2-L1-B13 A2-L2-B1 A2-L2-B2 A2-L2-B3 A2-L2-B4 A2-L2-B5 A2-L2-B6 A2-L2-B7 A2-L2-B8 A2-L2-B9 A2-L2-B10 A2-L2-B11 A2-L2-B12 A2-L2-B13 A2-L3-B1 A2-L3-B2 A2-L3-B3 A2-L3-B4 A2-L3-B5 A2-L3-B6 A2-L3-B7 A2-L3-B8 A2-L3-B9 A2-L3-B10 A2-L3-B11 A2-L3-B12 A2-L3-B13 A2-L4-B1 A2-L4-B2 A2-L4-B3 A2-L4-B4 A2-L4-B5 A2-L4-B6 A2-L4-B7 A2-L4-B8 A2-L4-B9 A2-L4-B10 A2-L4-B11 A2-L4-B12 A2-L4-B13 A2-L5-B1 A2-L5-B2 A2-L5-B3 A2-L5-B4 A2-L5-B5 A2-L5-B6 A2-L5-B7 A2-L5-B8 A2-L5-B9 A2-L5-B10 A2-L5-B11 A2-L5-B12 A2-L5-B13 A2-L6-B1 A2-L6-B2 A2-L6-B3 A2-L6-B4 A2-L6-B5 A2-L6-B6 A2-L6-B7 A2-L6-B8 A2-L6-B9 A2-L6-B10 A2-L6-B11 A2-L6-B12 A2-L6-B13 A2-L7-B1 A2-L7-B2 A2-L7-B3 A2-L7-B4 A2-L7-B5 A2-L7-B6 A2-L7-B7 A2-L7-B8 A2-L7-B9 A2-L7-B10 A2-L7-B11 A2-L7-B12 A2-L7-B13 A2-L8-B1 A2-L8-B2 A2-L8-B3 A2-L8-B4 A2-L8-B5 A2-L8-B6 A2-L8-B7 A2-L8-B8 A2-L8-B9 A2-L8-B10 A2-L8-B11 A2-L8-B12 A2-L8-B13 A2-L9-B1 A2-L9-B2 A2-L9-B3 A2-L9-B7 A2-L9-B8 A2-L9-B9 A2-L9-B11 A2-L9-B13 A2-L10-B1 A2-L10-B2 A2-L10-B3 A2-L10-B4 A2-L10-B5 A2-L10-B6 A2-L10-B7 A2-L10-B8 A2-L10-B9 A2-L10-B10 A2-L10-B11 A2-L10-B12 A2-L10-B13 A2-L11-B1 A2-L11-B2 A2-L11-B3 A2-L11-B4 A2-L11-B5 A2-L11-B6 A2-L11-B7 A2-L11-B8 A2-L11-B9 A2-L11-B10 A2-L11-B11 A2-L11-B12 A2-L11-B13 A2-L12-B1 A2-L12-B2 A2-L12-B3 A2-L12-B7 A2-L12-B8 A2-L12-B9 A2-L12-B11 A2-L12-B13 A2-L13-B1 A2-L13-B2 A2-L13-B3 A2-L13-B4 A2-L13-B5 A2-L13-B6 A2-L13-B7 A2-L13-B8 A2-L13-B9 A2-L13-B10 A2-L13-B11 A2-L13-B12 A2-L13-B13 A2-L14-B1 A2-L14-B2 A2-L14-B3 A2-L14-B4 A2-L14-B5 A2-L14-B6 A2-L14-B7 A2-L14-B8 A2-L14-B9 A2-L14-B10 A2-L14-B11 A2-L14-B12 A2-L14-B13 A2-L15-B1 A2-L15-B2 A2-L15-B3 A2-L15-B4 A2-L15-B5 A2-L15-B6 A2-L15-B7 A2-L15-B8 A2-L15-B9 A2-L15-B10 A2-L15-B11 A2-L15-B12 A2-L15-B13 A2-L16-B1 A2-L16-B2 A2-L16-B3 A2-L16-B4 A2-L16-B5 A2-L16-B6 A2-L16-B7 A2-L16-B8 A2-L16-B9 A2-L16-B10 A2-L16-B11 A2-L16-B12 A2-L16-B13 A2-L17-B1 A2-L17-B2 A2-L17-B3 A2-L17-B7 A2-L17-B8 A2-L17-B9 A2-L17-B11 A2-L17-B13 A2-L18-B1 A2-L18-B2 A2-L18-B3 A2-L18-B4 A2-L18-B5 A2-L18-B6 A2-L18-B7 A2-L18-B8 A2-L18-B9 A2-L18-B10 A2-L18-B11 A2-L18-B12 A2-L18-B13 A2-L19-B1 A2-L19-B2 A2-L19-B3 A2-L19-B4 A2-L19-B5 A2-L19-B6 A2-L19-B7 A2-L19-B8 A2-L19-B9 A2-L19-B10 A2-L19-B11 A2-L19-B12 A2-L19-B13 A2-L20-B1 A2-L20-B2 A2-L20-B3 A2-L20-B4 A2-L20-B5 A2-L20-B6 A2-L20-B7 A2-L20-B8 A2-L20-B9 A2-L20-B10 A2-L20-B11 A2-L20-B12 A2-L20-B13 A2-L21-B1 A2-L21-B2 A2-L21-B3 A2-L21-B4 A2-L21-B5 A2-L21-B6 A2-L21-B7 A2-L21-B8 A2-L21-B9 A2-L21-B10 A2-L21-B11 A2-L21-B12 A2-L21-B13 A2-L22-B1 A2-L22-B2 A2-L22-B3 A2-L22-B4 A2-L22-B5 A2-L22-B6 A2-L22-B7 A2-L22-B8 A2-L22-B9 A2-L22-B10 A2-L22-B11 A2-L22-B12 A2-L22-B13 A2-L23-B1 A2-L23-B2 A2-L23-B3 A2-L23-B4 A2-L23-B5 A2-L23-B6 A2-L23-B7 A2-L23-B8 A2-L23-B9 A2-L23-B10 A2-L23-B11 A2-L23-B12 A2-L23-B13 A2-L24-B1 A2-L24-B2 A2-L24-B3 A2-L24-B4 A2-L24-B5 A2-L24-B6 A2-L24-B7 A2-L24-B8 A2-L24-B9 A2-L24-B10 A2-L24-B11 A2-L24-B12 A2-L24-B13 A2-L25-B1 A2-L25-B2 A2-L25-B3 A2-L25-B4 A2-L25-B5 A2-L25-B6 A2-L25-B7 A2-L25-B8 A2-L25-B9 A2-L25-B10 A2-L25-B11 A2-L25-B12 A2-L25-B13 A2-L26-B1 A2-L26-B2 A2-L26-B3 A2-L26-B4 A2-L26-B5 A2-L26-B6 A2-L26-B7 A2-L26-B8 A2-L26-B9 A2-L26-B10 A2-L26-B11 A2-L26-B12 A2-L26-B13 A2-L27-B1 A2-L27-B2 A2-L27-B3 A2-L27-B4 A2-L27-B5 A2-L27-B6 A2-L27-B7 A2-L27-B8 A2-L27-B9 A2-L27-B10 A2-L27-B11 A2-L27-B12 A2-L27-B13 A2-L28-B1 A2-L28-B2 A2-L28-B3 A2-L28-B4 A2-L28-B5 A2-L28-B6 A2-L28-B7 A2-L28-B8 A2-L28-B9 A2-L28-B10 A2-L28-B11 A2-L28-B12 A2-L28-B13 A2-L29-B1 A2-L29-B2 A2-L29-B3 A2-L29-B4 A2-L29-B5 A2-L29-B6 A2-L29-B7 A2-L29-B8 A2-L29-B9 A2-L29-B10 A2-L29-B11 A2-L29-B12 A2-L29-B13 A2-L30-B1 A2-L30-B2 A2-L30-B3 A2-L30-B4 A2-L30-B5 A2-L30-B6 A2-L30-B7 A2-L30-B8 A2-L30-B9 A2-L30-B10 A2-L30-B11 A2-L30-B12 A2-L30-B13 A2-L31-B1 A2-L31-B2 A2-L31-B3 A2-L31-B4 A2-L31-B5 A2-L31-B6 A2-L31-B7 A2-L31-B8 A2-L31-B9 A2-L31-B10 A2-L31-B11 A2-L31-B12 A2-L31-B13 A2-L32-B1 A2-L32-B2 A2-L32-B3 A2-L32-B7 A2-L32-B8 A2-L32-B9 A2-L32-B11 A2-L32-B13 A2-L33-B1 A2-L33-B2 A2-L33-B3 A2-L33-B4 A2-L33-B5 A2-L33-B6 A2-L33-B7 A2-L33-B8 A2-L33-B9 A2-L33-B10 A2-L33-B11 A2-L33-B12 A2-L33-B13 A2-L34-B1 A2-L34-B2 A2-L34-B3 A2-L34-B7 A2-L34-B8 A2-L34-B9 A2-L34-B11 A2-L34-B13 A2-L35-B1 A2-L35-B2 A2-L35-B3 A2-L35-B4 A2-L35-B5 A2-L35-B6 A2-L35-B7 A2-L35-B8 A2-L35-B9 A2-L35-B10 A2-L35-B11 A2-L35-B12 A2-L35-B13 A2-L36-B1 A2-L36-B2 A2-L36-B3 A2-L36-B4 A2-L36-B5 A2-L36-B6 A2-L36-B7 A2-L36-B8 A2-L36-B9 A2-L36-B10 A2-L36-B11 A2-L36-B12 A2-L36-B13 A2-L37-B1 A2-L37-B2 A2-L37-B3 A2-L37-B4 A2-L37-B5 A2-L37-B6 A2-L37-B7 A2-L37-B8 A2-L37-B9 A2-L37-B10 A2-L37-B11 A2-L37-B12 A2-L37-B13 A2-L38-B1 A2-L38-B2 A2-L38-B3 A2-L38-B4 A2-L38-B5 A2-L38-B6 A2-L38-B7 A2-L38-B8 A2-L38-B9 A2-L38-B10 A2-L38-B11 A2-L38-B12 A2-L38-B13 A2-L39-B1 A2-L39-B2 A2-L39-B3 A2-L39-B4 A2-L39-B5 A2-L39-B6 A2-L39-B7 A2-L39-B8 A2-L39-B9 A2-L39-B10 A2-L39-B11 A2-L39-B12 A2-L39-B13 A2-L40-B1 A2-L40-B2 A2-L40-B3 A2-L40-B4 A2-L40-B5 A2-L40-B6 A2-L40-B7 A2-L40-B8 A2-L40-B9 A2-L40-B10 A2-L40-B11 A2-L40-B12 A2-L40-B13 A2-L41-B1 A2-L41-B2 A2-L41-B3 A2-L41-B4 A2-L41-B5 A2-L41-B6 A2-L41-B7 A2-L41-B8 A2-L41-B9 A2-L41-B10 A2-L41-B11 A2-L41-B12 A2-L41-B13 A2-L42-B1 A2-L42-B2 A2-L42-B3 A2-L42-B4 A2-L42-B5 A2-L42-B6 A2-L42-B7 A2-L42-B8 A2-L42-B9 A2-L42-B10 A2-L42-B11 A2-L42-B12 A2-L42-B13 A2-L43-B1 A2-L43-B2 A2-L43-B3 A2-L43-B4 A2-L43-B5 A2-L43-B6 A2-L43-B7 A2-L43-B8 A2-L43-B9 A2-L43-B10 A2-L43-B11 A2-L43-B12 A2-L43-B13 A2-L44-B1 A2-L44-B2 A2-L44-B3 A2-L44-B7 A2-L44-B8 A2-L44-B9 A2-L44-B11 A2-L44-B13 A3-L1-B1 A3-L1-B2 A3-L1-B3 A3-L1-B4 A3-L1-B5 A3-L1-B6 A3-L1-B7 A3-L1-B8 A3-L1-B9 A3-L1-B10 A3-L1-B11 A3-L1-B12 A3-L1-B13 A3-L2-B1 A3-L2-B2 A3-L2-B3 A3-L2-B4 A3-L2-B5 A3-L2-B6 A3-L2-B7 A3-L2-B8 A3-L2-B9 A3-L2-B10 A3-L2-B11 A3-L2-B12 A3-L2-B13 A3-L3-B1 A3-L3-B2 A3-L3-B3 A3-L3-B4 A3-L3-B5 A3-L3-B6 A3-L3-B7 A3-L3-B8 A3-L3-B9 A3-L3-B10 A3-L3-B11 A3-L3-B12 A3-L3-B13 A3-L4-B1 A3-L4-B2 A3-L4-B3 A3-L4-B4 A3-L4-B5 A3-L4-B6 A3-L4-B7 A3-L4-B8 A3-L4-B9 A3-L4-B10 A3-L4-B11 A3-L4-B12 A3-L4-B13 A3-L5-B1 A3-L5-B2 A3-L5-B3 A3-L5-B4 A3-L5-B5 A3-L5-B6 A3-L5-B7 A3-L5-B8 A3-L5-B9 A3-L5-B10 A3-L5-B11 A3-L5-B12 A3-L5-B13 A3-L6-B1 A3-L6-B2 A3-L6-B3 A3-L6-B4 A3-L6-B5 A3-L6-B6 A3-L6-B7 A3-L6-B8 A3-L6-B9 A3-L6-B10 A3-L6-B11 A3-L6-B12 A3-L6-B13 A3-L7-B1 A3-L7-B2 A3-L7-B3 A3-L7-B4 A3-L7-B5 A3-L7-B6 A3-L7-B7 A3-L7-B8 A3-L7-B9 A3-L7-B10 A3-L7-B11 A3-L7-B12 A3-L7-B13 A3-L8-B1 A3-L8-B2 A3-L8-B3 A3-L8-B4 A3-L8-B5 A3-L8-B6 A3-L8-B7 A3-L8-B8 A3-L8-B9 A3-L8-B10 A3-L8-B11 A3-L8-B12 A3-L8-B13 A3-L9-B1 A3-L9-B2 A3-L9-B3 A3-L9-B7 A3-L9-B8 A3-L9-B9 A3-L9-B11 A3-L9-B13 A3-L10-B1 A3-L10-B2 A3-L10-B3 A3-L10-B4 A3-L10-B5 A3-L10-B6 A3-L10-B7 A3-L10-B8 A3-L10-B9 A3-L10-B10 A3-L10-B11 A3-L10-B12 A3-L10-B13 A3-L11-B1 A3-L11-B2 A3-L11-B3 A3-L11-B4 A3-L11-B5 A3-L11-B6 A3-L11-B7 A3-L11-B8 A3-L11-B9 A3-L11-B10 A3-L11-B11 A3-L11-B12 A3-L11-B13 A3-L12-B1 A3-L12-B2 A3-L12-B3 A3-L12-B7 A3-L12-B8 A3-L12-B9 A3-L12-B11 A3-L12-B13 A3-L13-B1 A3-L13-B2 A3-L13-B3 A3-L13-B4 A3-L13-B5 A3-L13-B6 A3-L13-B7 A3-L13-B8 A3-L13-B9 A3-L13-B10 A3-L13-B11 A3-L13-B12 A3-L13-B13 A3-L14-B1 A3-L14-B2 A3-L14-B3 A3-L14-B4 A3-L14-B5 A3-L14-B6 A3-L14-B7 A3-L14-B8 A3-L14-B9 A3-L14-B10 A3-L14-B11 A3-L14-B12 A3-L14-B13 A3-L15-B1 A3-L15-B2 A3-L15-B3 A3-L15-B4 A3-L15-B5 A3-L15-B6 A3-L15-B7 A3-L15-B8 A3-L15-B9 A3-L15-B10 A3-L15-B11 A3-L15-B12 A3-L15-B13 A3-L16-B1 A3-L16-B2 A3-L16-B3 A3-L16-B4 A3-L16-B5 A3-L16-B6 A3-L16-B7 A3-L16-B8 A3-L16-B9 A3-L16-B10 A3-L16-B11 A3-L16-B12 A3-L16-B13 A3-L17-B1 A3-L17-B2 A3-L17-B3 A3-L17-B7 A3-L17-B8 A3-L17-B9 A3-L17-B11 A3-L17-B13 A3-L18-B1 A3-L18-B2 A3-L18-B3 A3-L18-B4 A3-L18-B5 A3-L18-B6 A3-L18-B7 A3-L18-B8 A3-L18-B9 A3-L18-B10 A3-L18-B11 A3-L18-B12 A3-L18-B13 A3-L19-B1 A3-L19-B2 A3-L19-B3 A3-L19-B4 A3-L19-B5 A3-L19-B6 A3-L19-B7 A3-L19-B8 A3-L19-B9 A3-L19-B10 A3-L19-B11 A3-L19-B12 A3-L19-B13 A3-L20-B1 A3-L20-B2 A3-L20-B3 A3-L20-B4 A3-L20-B5 A3-L20-B6 A3-L20-B7 A3-L20-B8 A3-L20-B9 A3-L20-B10 A3-L20-B11 A3-L20-B12 A3-L20-B13 A3-L21-B1 A3-L21-B2 A3-L21-B3 A3-L21-B4 A3-L21-B5 A3-L21-B6 A3-L21-B7 A3-L21-B8 A3-L21-B9 A3-L21-B10 A3-L21-B11 A3-L21-B12 A3-L21-B13 A3-L22-B1 A3-L22-B2 A3-L22-B3 A3-L22-B4 A3-L22-B5 A3-L22-B6 A3-L22-B7 A3-L22-B8 A3-L22-B9 A3-L22-B10 A3-L22-B11 A3-L22-B12 A3-L22-B13 A3-L23-B1 A3-L23-B2 A3-L23-B3 A3-L23-B4 A3-L23-B5 A3-L23-B6 A3-L23-B7 A3-L23-B8 A3-L23-B9 A3-L23-B10 A3-L23-B11 A3-L23-B12 A3-L23-B13 A3-L24-B1 A3-L24-B2 A3-L24-B3 A3-L24-B4 A3-L24-B5 A3-L24-B6 A3-L24-B7 A3-L24-B8 A3-L24-B9 A3-L24-B10 A3-L24-B11 A3-L24-B12 A3-L24-B13 A3-L25-B1 A3-L25-B2 A3-L25-B3 A3-L25-B4 A3-L25-B5 A3-L25-B6 A3-L25-B7 A3-L25-B8 A3-L25-B9 A3-L25-B10 A3-L25-B11 A3-L25-B12 A3-L25-B13 A3-L26-B1 A3-L26-B2 A3-L26-B3 A3-L26-B4 A3-L26-B5 A3-L26-B6 A3-L26-B7 A3-L26-B8 A3-L26-B9 A3-L26-B10 A3-L26-B11 A3-L26-B12 A3-L26-B13 A3-L27-B1 A3-L27-B2 A3-L27-B3 A3-L27-B4 A3-L27-B5 A3-L27-B6 A3-L27-B7 A3-L27-B8 A3-L27-B9 A3-L27-B10 A3-L27-B11 A3-L27-B12 A3-L27-B13 A3-L28-B1 A3-L28-B2 A3-L28-B3 A3-L28-B4 A3-L28-B5 A3-L28-B6 A3-L28-B7 A3-L28-B8 A3-L28-B9 A3-L28-B10 A3-L28-B11 A3-L28-B12 A3-L28-B13 A3-L29-B1 A3-L29-B2 A3-L29-B3 A3-L29-B4 A3-L29-B5 A3-L29-B6 A3-L29-B7 A3-L29-B8 A3-L29-B9 A3-L29-B10 A3-L29-B11 A3-L29-B12 A3-L29-B13 A3-L30-B1 A3-L30-B2 A3-L30-B3 A3-L30-B4 A3-L30-B5 A3-L30-B6 A3-L30-B7 A3-L30-B8 A3-L30-B9 A3-L30-B10 A3-L30-B11 A3-L30-B12 A3-L30-B13 A3-L31-B1 A3-L31-B2 A3-L31-B3 A3-L31-B4 A3-L31-B5 A3-L31-B6 A3-L31-B7 A3-L31-B8 A3-L31-B9 A3-L31-B10 A3-L31-B11 A3-L31-B12 A3-L31-B13 A3-L32-B1 A3-L32-B2 A3-L32-B3 A3-L32-B7 A3-L32-B8 A3-L32-B9 A3-L32-B11 A3-L32-B13 A3-L33-B1 A3-L33-B2 A3-L33-B3 A3-L33-B4 A3-L33-B5 A3-L33-B6 A3-L33-B7 A3-L33-B8 A3-L33-B9 A3-L33-B10 A3-L33-B11 A3-L33-B12 A3-L33-B13 A3-L34-B1 A3-L34-B2 A3-L34-B3 A3-L34-B7 A3-L34-B8 A3-L34-B9 A3-L34-B11 A3-L34-B13 A3-L35-B1 A3-L35-B2 A3-L35-B3 A3-L35-B4 A3-L35-B5 A3-L35-B6 A3-L35-B7 A3-L35-B8 A3-L35-B9 A3-L35-B10 A3-L35-B11 A3-L35-B12 A3-L35-B13 A3-L36-B1 A3-L36-B2 A3-L36-B3 A3-L36-B4 A3-L36-B5 A3-L36-B6 A3-L36-B7 A3-L36-B8 A3-L36-B9 A3-L36-B10 A3-L36-B11 A3-L36-B12 A3-L36-B13 A3-L37-B1 A3-L37-B2 A3-L37-B3 A3-L37-B4 A3-L37-B5 A3-L37-B6 A3-L37-B7 A3-L37-B8 A3-L37-B9 A3-L37-B10 A3-L37-B11 A3-L37-B12 A3-L37-B13 A3-L38-B1 A3-L38-B2 A3-L38-B3 A3-L38-B4 A3-L38-B5 A3-L38-B6 A3-L38-B7 A3-L38-B8 A3-L38-B9 A3-L38-B10 A3-L38-B11 A3-L38-B12 A3-L38-B13 A3-L39-B1 A3-L39-B2 A3-L39-B3 A3-L39-B4 A3-L39-B5 A3-L39-B6 A3-L39-B7 A3-L39-B8 A3-L39-B9 A3-L39-B10 A3-L39-B11 A3-L39-B12 A3-L39-B13 A3-L40-B1 A3-L40-B2 A3-L40-B3 A3-L40-B4 A3-L40-B5 A3-L40-B6 A3-L40-B7 A3-L40-B8 A3-L40-B9 A3-L40-B10 A3-L40-B11 A3-L40-B12 A3-L40-B13 A3-L41-B1 A3-L41-B2 A3-L41-B3 A3-L41-B4 A3-L41-B5 A3-L41-B6 A3-L41-B7 A3-L41-B8 A3-L41-B9 A3-L41-B10 A3-L41-B11 A3-L41-B12 A3-L41-B13 A3-L42-B1 A3-L42-B2 A3-L42-B3 A3-L42-B4 A3-L42-B5 A3-L42-B6 A3-L42-B7 A3-L42-B8 A3-L42-B9 A3-L42-B10 A3-L42-B11 A3-L42-B12 A3-L42-B13 A3-L43-B1 A3-L43-B2 A3-L43-B3 A3-L43-B4 A3-L43-B5 A3-L43-B6 A3-L43-B7 A3-L43-B8 A3-L43-B9 A3-L43-B10 A3-L43-B11 A3-L43-B12 A3-L43-B13 A3-L44-B1 A3-L44-B2 A3-L44-B3 A3-L44-B7 A3-L44-B8 A3-L44-B9 A3-L44-B11 A3-L44-B13 A1-L20-B14 A1-L21-B14 A1-L22-B14 A1-L23-B14 A1-L24-B14 A1-L2-B14 A1-L3-B14 A1-L45-B14 A1-L20-B15 A1-L21-B15 A1-L22-B15 A1-L23-B15 A1-L24-B15 A1-L2-B15 A1-L3-B15 A1-L45-B15 A1-L20-B16 A1-L21-B16 A1-L22-B16 A1-L23-B16 A1-L24-B16 A1-L2-B16 A1-L3-B16 A1-L45-B16 A1-L20-B17 A1-L21-B17 A1-L22-B17 A1-L23-B17 A1-L24-B17 A1-L2-B17 A1-L3-B17 A1-L45-B17 A1-L20-B18 A1-L21-B18 A1-L22-B18 A1-L23-B18 A1-L24-B18 A1-L2-B18 A1-L3-B18 A1-L45-B18 A1-L20-B19 A1-L21-B19 A1-L22-B19 A1-L23-B19 A1-L24-B19 A1-L2-B19 A1-L3-B19 A1-L45-B19 A4-L46-B10 A4-L18-B10 A4-L19-B10 A4-L46-B15 A4-L18-B15 A4-L19-B15 A4-L46-B16 A4-L18-B16 A4-L19-B16 A4-L46-B6 A4-L18-B6 A4-L19-B6 A1-L45-B10

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.
 2. A compound selected from:

or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.
 3. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
 5. A method for the treatment or prevention of a condition which can be ameliorated by inhibition of PARP in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of claim 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.
 6. A method of treating or preventing cancer, comprising administering an effective amount of a compound of claim 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, to an individual in need thereof.
 7. The method of claim 5, wherein the administering comprises oral administration.
 8. The method of claim 5, further comprising administering an additional chemotherapeutic agent.
 9. The method of claim 8, wherein the additional chemotherapeutic agent is cisplatin etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, taxotere, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778123, BMS 214662, gefitinib, erlotinib hydrochloride, antibodies to EGFR, imatinib, intron, cytarabine, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, vinblastine, vincristine, vindesine, bleomycin, doxorubicin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide, 17α-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrolacetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexxar, velcade, zevalin, trisenox, xeloda, vinorelbine, porfimer, cetuximab, liposomal, Thiotepa, Altretamine, melphalan, Trastuzumab, lerozole, fulvestrant, exemestane, ifosfomide, rituximab, C225, Campath, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP 16), tamoxifen, raloxifene, estrogen receptor binding agents, paclitaxel, gemcitabine, navelbine, farnesyl-protein transferase inhibitors, transplatinum, 5-fluorouracil, vincristine, vinblastine methotrexate, or an analog or derivative thereof.
 10. The method of claim 5, further comprising administering radiotherapy to the patient.
 11. The method of claim 5, wherein the cancer is a BRCA positive cancer.
 12. The method of claim 5, wherein the cancer is a solid tumor.
 13. The method of claim 5, wherein the cancer is a cancer affecting B cells.
 14. The method of claim 5, wherein the cancer is a blood cancer, lung cancer, breast cancer, fallopian tube cancer, brain cancer, head and neck cancer, esophageal cancer, ovarian cancer, pancreatic cancer, peritoneal cancer, prostate cancer or skin cancer.
 15. The method of claim 14, wherein the cancer is liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphomas, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast carcinoma, ovarian carcinoma, lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, soft-tissue sarcoma, chronic lymphocytic leukemia, primary macroglobulinemia, bladder carcinoma, chronic granulocytic leukemia, primary brain carcinoma, malignant melanoma, small-cell lung carcinoma, stomach carcinoma, colon carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, malignant melanoma, choriocarcinoma, mycosis fungoide, head neck carcinoma, osteogenic sarcoma, pancreatic carcinoma, acute granulocytic leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial carcinoma, polycythemia vera, essential thrombocytosis, adrenal cortex carcinoma, skin cancer, or prostatic carcinoma.
 16. The method of claim 15, wherein the cancer is bladder cancer, breast cancer, fallopian tube cancer, ovarian cancer, prostate cancer, peritoneal cancer, testicular cancer, endometrial cancer, or uterine cancer.
 17. A method of treating or preventing an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound of claim 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, to an individual in need thereof.
 18. The method of claim 17, wherein the cancer is prostate, breast, triple negative breast cancer, bladder, or liver cancer.
 19. The method of claim 17, wherein the androgen receptor-targeting epitope comprises an androgen receptor agonist, a selective androgen-receptor modulator (S ARM), an androgen receptor antagonist, a selective estrogen receptor modulator (SERM), an estrogen receptor antagonist, a progestin, or an estrogen.
 20. The method of claim 19, wherein the androgen receptor-targeting epitope comprises enobosarm, bicalutamide, flutamide, nilutamide, enzalutamide, tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, estramustine, ketoconazole, abiraterone, darolutamide, or an analog thereof.
 21. A method of treating or preventing an estrogen and/or progesterone receptor overexpressing cancer, comprising administering an effective amount of a compound of claim 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, to an individual in need thereof.
 22. The method of claim 21, wherein the cancer is breast, uterine, or ovarian cancer.
 23. A method of treating or preventing a glucocorticoid receptor overexpressing cancer, comprising administering an effective amount of a compound of claim 1, or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof, to an individual in need thereof.
 24. The method of claim 23, wherein the cancer is prostate, breast, uterine, or ovarian cancer. 